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Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

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  • First Online:
DNA Replication

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1042))

Abstract

Chromosome fragile sites are a fascinating cytogenetic phenomenon now widely implicated in a slew of human diseases ranging from neurological disorders to cancer. Yet, the paths leading to these revelations were far from direct, and the number of fragile sites that have been molecularly cloned with known disease-associated genes remains modest. Moreover, as more fragile sites were being discovered, research interests in some of the earliest discovered fragile sites ebbed away, leaving a number of unsolved mysteries in chromosome biology. In this review we attempt to recount some of the early discoveries of fragile sites and highlight those phenomena that have eluded intense scrutiny but remain extremely relevant in our understanding of the mechanisms of chromosome fragility. We then survey the literature for disease association for a comprehensive list of fragile sites. We also review recent studies addressing the underlying cause of chromosome fragility while highlighting some ongoing debates. We report an observed enrichment for R-loop forming sequences in fragile site-associated genes than genomic average. Finally, we will leave the reader with some lingering questions to provoke discussion and inspire further scientific inquiries.

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References

  • Amarose AP, Huttenlocher PR, Sprudzs RM, Laitsch TJ, Pettenati MJ (1987) A heritable fragile 12q24.13 segregating in a family with the fragile X chromosome. Hum Genet 75:4–6

    CAS  PubMed  Google Scholar 

  • Ambroziak W, Koziorowski D, Duszyc K, Gorka-Skoczylas P, Potulska-Chromik A, Slawek J, Hoffman-Zacharska D (2015) Genomic instability in the PARK2 locus is associated with Parkinson’s disease. J Appl Genet 56:451–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arlt MF, Miller DE, Beer DG, Glover TW (2002) Molecular characterization of FRAXB and comparative common fragile site instability in cancer cells. Genes Chromosom Cancer 33:82–92

    Article  CAS  PubMed  Google Scholar 

  • Arlt MF, Durkin SG, Ragland RL, Glover TW (2006) Common fragile sites as targets for chromosome rearrangements. DNA Repair 5:1126–1135

    Article  CAS  PubMed  Google Scholar 

  • Baranello L, Kouzine F, Wojtowicz D, Cui K, Przytycka TM, Zhao K, Levens D (2014) DNA break mapping reveals topoisomerase II activity genome-wide. Int J Mol Sci 15:13111–13122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbi G, Steinbach P, Vogel W (1984) Nonrandom distribution of methotrexate-induced aberrations on human chromosomes. Detection of further folic acid sensitive fragile sites. Human Genetics 68:290–294

    Article  CAS  PubMed  Google Scholar 

  • Barletta C, Ragusa RM, Garofalo G, Scillato F, Ruggeri M (1991) Segregation analysis of autosomal fragile sites in three families with the fragile X chromosome. Ann Genet 34:111–114

    CAS  PubMed  Google Scholar 

  • Barlow JH, Faryabi RB, Callen E, Wong N, Malhowski A, Chen HT, Gutierrez-Cruz G, Sun HW, McKinnon P, Wright G et al (2013) Identification of early replicating fragile sites that contribute to genome instability. Cell 152:620–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bell MV, Hirst MC, Nakahori Y, MacKinnon RN, Roche A, Flint TJ, Jacobs PA, Tommerup N, Tranebjaerg L, Froster-Iskenius U et al (1991) Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell 64:861–866

    Article  CAS  PubMed  Google Scholar 

  • Bensaid M, Melko M, Bechara EG, Davidovic L, Berretta A, Catania MV, Gecz J, Lalli E, Bardoni B (2009) FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure. Nucleic Acids Res 37:1269–1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berois N, Gattolliat CH, Barrios E, Capandeguy L, Douc-Rasy S, Valteau-Couanet D, Benard J, Osinaga E (2013) GALNT9 gene expression is a prognostic marker in neuroblastoma patients. Clin Chem 59:225–233

    Article  CAS  PubMed  Google Scholar 

  • Bettex M, Graf B, Winkler B, Gerber-Huber S (1998) Oro-palatal dysplasia Bettex-Graf–a new syndrome. Eur J Pediatr Surg 8:4–8

    Article  CAS  PubMed  Google Scholar 

  • Bharadwaj R, Jiang Y, Mao W, Jakovcevski M, Dincer A, Krueger W, Garbett K, Whittle C, Tushir JS, Liu J et al (2013) Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. J Neurosci 33:11839–11851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A (2014) BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511:362–365

    Article  CAS  PubMed  Google Scholar 

  • Bhowmick R, Minocherhomji S, Hickson ID (2016) RAD52 facilitates mitotic DNA synthesis following replication stress. Mol Cell 64:1117–1126

    Article  CAS  PubMed  Google Scholar 

  • Blumrich A, Zapatka M, Brueckner LM, Zheglo D, Schwab M, Savelyeva L (2011) The FRA2C common fragile site maps to the borders of MYCN amplicons in neuroblastoma and is associated with gross chromosomal rearrangements in different cancers. Hum Mol Genet 20:1488–1501

    Article  CAS  PubMed  Google Scholar 

  • Bodelon C, Untereiner ME, Machiela MJ, Vinokurova S, Wentzensen N (2016) Genomic characterization of viral integration sites in HPV-related cancers. Int J Cancer 139:2001–2011

    Article  CAS  PubMed  Google Scholar 

  • Bosco N, Pelliccia F, Rocchi A (2010) Characterization of FRA7B, a human common fragile site mapped at the 7p chromosome terminal region. Cancer Genet Cytogenet 202:47–52

    Article  CAS  PubMed  Google Scholar 

  • Bozza M, Bernardini L, Novelli A, Brovedani P, Moretti E, Canapicchi R, Doccini V, Filippi T, Battaglia A (2013) 6p25 interstitial deletion in two dizygotic twins with gyral pattern anomaly and speech and language disorder. Eur J Paediatr Neurol 17:225–231

    Article  PubMed  Google Scholar 

  • Bryan DS, Ransom M, Adane B, York K, Hesselberth JR (2014) High resolution mapping of modified DNA nucleobases using excision repair enzymes. Genome Res 24:1534–1542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brys M, Migdalska-Sek M, Pastuszak-Lewandoska D, Forma E, Czarnecka K, Domanska D, Nawrot E, Wilkosz J, Rozanski W, Brzezianska E (2013) Diagnostic value of DNA alteration: loss of heterozygosity or allelic imbalance-promising for molecular staging of prostate cancers. Med Oncol 30:391

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Burrow AA, Marullo A, Holder LR, Wang YH (2010) Secondary structure formation and DNA instability at fragile site FRA16B. Nucleic Acids Res 38:2865–2877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Callahan G, Denison SR, Phillips LA, Shridhar V, Smith DI (2003) Characterization of the common fragile site FRA9E and its potential role in ovarian cancer. Oncogene 22:590–601

    Article  CAS  PubMed  Google Scholar 

  • Capello D, Scandurra M, Poretti G, Rancoita PM, Mian M, Gloghini A, Deambrogi C, Martini M, Rossi D, Greiner TC et al (2010) Genome wide DNA-profiling of HIV-related B-cell lymphomas. Br J Haematol 148:245–255

    Article  CAS  PubMed  Google Scholar 

  • Chen CH, Shih HH, Wang-Wuu S, Tai JJ, Wuu KD (1998) Chromosomal fragile site expression in lymphocytes from patients with schizophrenia. Hum Genet 103:702–706

    Article  CAS  PubMed  Google Scholar 

  • Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA et al (2004) DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74:1128–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi J, Majima T (2011) Conformational changes of non-B DNA. Chem Soc Rev 40:5893–5909

    Article  CAS  PubMed  Google Scholar 

  • Conley ME, Spinner NB, Emanuel BS, Nowell PC, Nichols WW (1986) A chromosomal breakage syndrome with profound immunodeficiency. Blood 67:1251–1256

    CAS  PubMed  Google Scholar 

  • Court Brown WM (1966) Chromosome studies on adults. Cambridge U.P, Galton Laboratory, University of London, Cambridge

    Google Scholar 

  • Crosetto N, Mitra A, Silva MJ, Bienko M, Dojer N, Wang Q, Karaca E, Chiarle R, Skrzypczak M, Ginalski K et al (2013) Nucleotide-resolution DNA double-strand break mapping by next-generation sequencing. Nat Methods 10:361–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’Angelo CS, Moller Dos Santos MF, Alonso LG, Koiffmann CP (2015) Two new cases of 1p21.3 deletions and an unbalanced translocation t(8;12) among individuals with syndromic obesity. Mol Syndromology 6:63–70

    Article  CAS  Google Scholar 

  • Debacker K, Kooy RF (2007) Fragile sites and human disease. Hum Mol Genet 16 (Spec No. 2):R150–R158

    Google Scholar 

  • Debacker K, Winnepenninckx B, Ben-Porat N, FitzPatrick D, Van Luijk R, Scheers S, Kerem B, Frank Kooy R (2007) FRA18C: a new aphidicolin-inducible fragile site on chromosome 18q22, possibly associated with in vivo chromosome breakage. J Med Genet 44:347–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dekaban A (1965) Persisting clone of cells with an abnormal chromosome in a woman previously irradiated. J Nucl Med 6:740–746

    CAS  PubMed  Google Scholar 

  • Demirhan O, Tastemir D, Sertdemir Y (2006) Chromosomal fragile sites in schizophrenic patients. Genetika 42:985–992

    CAS  PubMed  Google Scholar 

  • Demirhan O, Tastemir D, Sertdemir Y (2009) The expression of folate sensitive fragile sites in patients with bipolar disorder. Yonsei Med J 50:137–141

    Article  PubMed  PubMed Central  Google Scholar 

  • Dietrich A, Kioschis P, Monaco AP, Gross B, Korn B, Williams SV, Sheer D, Heitz D, Oberle I, Toniolo D et al (1991) Molecular cloning and analysis of the fragile X region in man. Nucleic Acids Res 19:2567–2572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dillon LW, Burrow AA, Wang YH (2010) DNA instability at chromosomal fragile sites in cancer. Curr Genomics 11:326–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dillon LW, Pierce LC, Ng MC, Wang YH (2013) Role of DNA secondary structures in fragile site breakage along human chromosome 10. Hum Mol Genet 22:1443–1456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dooley TP, Mitchison HM, Munroe PB, Probst P, Neal M, Siciliano MJ, Deng Z, Doggett NA, Callen DF, Gardiner RM et al (1994) Mapping of two phenol sulphotransferase genes, STP and STM, to 16p: candidate genes for Batten disease. Biochem Biophys Res Commun 205:482–489

    Article  CAS  PubMed  Google Scholar 

  • Dunner JA, Martin AO, Traisman ES, Traisman HS, Elias S (1983) Enhancement of a fra(16)(q22) with distamycin A: a family ascertained through an abnormal proposita. Am J Med Genet 16:277–284

    Article  CAS  PubMed  Google Scholar 

  • Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41:169–192

    Article  CAS  PubMed  Google Scholar 

  • El Achkar E, Gerbault-Seureau M, Muleris M, Dutrillaux B, Debatisse M (2005) Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites. Proc Natl Acad Sci U S A 102:18069–18074

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Engelman JA, Zhang XL, Lisanti MP (1998) Genes encoding human caveolin-1 and -2 are co-localized to the D7S522 locus (7q31.1), a known fragile site (FRA7G) that is frequently deleted in human cancers. FEBS Lett 436:403–410

    Article  CAS  PubMed  Google Scholar 

  • Fechter A, Buettel I, Kuehnel E, Savelyeva L, Schwab M (2007) Common fragile site FRA11G and rare fragile site FRA11B at 11q23.3 encompass distinct genomic regions. Genes Chromosom Cancer 46:98–106

    Article  CAS  PubMed  Google Scholar 

  • Ferber MJ, Eilers P, Schuuring E, Fenton JA, Fleuren GJ, Kenter G, Szuhai K, Smith DI, Raap AK, Brink AA (2004) Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papillomavirus integration cluster in FRA8C at 8q24.13. Cancer Genet Cytogenet 154:1–9

    Article  CAS  PubMed  Google Scholar 

  • Ferguson-Smith MA (1973) Inherited constriction fragility of chromosome 2. Ann Genet 16:29–34

    CAS  PubMed  Google Scholar 

  • Ferguson-Smith MA, Ferguson-Smith ME, Ellis PM, Dickson M (1962) The sites and relative frequencies of secondary constrictions in human somatic chromosomes. Cytogenetics 1:325–343

    Article  CAS  PubMed  Google Scholar 

  • Fry M, Loeb LA (1994) The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proc Natl Acad Sci U S A 91:4950–4954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu JF, Hsu JJ, Tang TC, Shih LY (2003) Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia. Genes Chromosom Cancer 37:214–219

    Article  CAS  PubMed  Google Scholar 

  • Fungtammasan A, Walsh E, Chiaromonte F, Eckert KA, Makova KD (2012) A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res 22:993–1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galloway JN, Nelson DL (2009) Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome. Futur Neurol 4:785

    Article  CAS  Google Scholar 

  • Gandhi M, Dillon LW, Pramanik S, Nikiforov YE, Wang YH (2010) DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells. Oncogene 29:2272–2280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao G, Kasperbauer JL, Tombers NM, Wang V, Mayer K, Smith DI (2014) A selected group of large common fragile site genes have decreased expression in oropharyngeal squamous cell carcinomas. Genes Chromosom Cancer 53:392–401

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Arocena D, Hagerman PJ (2010) Advances in understanding the molecular basis of FXTAS. Hum Mol Genet 19:R83–R89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginno PA, Lim YW, Lott PL, Korf I, Chedin F (2013) GC skew at the 5′ and 3′ ends of human genes links R-loop formation to epigenetic regulation and transcription termination. Genome Res 23:1590–1600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giraud F, Ayme S, Mattei JF, Mattei MG (1976) Constitutional chromosomal breakage. Hum Genet 34:125–136

    Article  CAS  PubMed  Google Scholar 

  • Glasser L, Meloni-Ehrig A, Joseph P, Mendiola J (2006) Benign chronic neutropenia with abnormalities involving 16q22, affecting mother and daughter. Am J Hematol 81:262–270

    Article  CAS  PubMed  Google Scholar 

  • Glover TW, Berger C, Coyle J, Echo B (1984) DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67:136–142

    Article  CAS  PubMed  Google Scholar 

  • Groh M, Gromak N (2014) Out of balance: R-loops in human disease. PLoS Genet 10:e1004630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Groh M, Lufino MM, Wade-Martins R, Gromak N (2014) R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet 10:e1004318

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Handt O, Sutherland GR, Richards RI (2000) Fragile sites and minisatellite repeat instability. Mol Genet Metab 70:99–105

    Article  CAS  PubMed  Google Scholar 

  • Hansen RS, Gartler SM, Scott CR, Chen SH, Laird CD (1992) Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum Mol Genet 1:571–578

    Article  CAS  PubMed  Google Scholar 

  • Hansen RS, Canfield TK, Lamb MM, Gartler SM, Laird CD (1993) Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell 73:1403–1409

    Article  CAS  PubMed  Google Scholar 

  • Harvey J, Judge C, Wiener S (1977) Familial X-linked mental retardation with an X chromosome abnormality. J Med Genet 14:46–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hatchi E, Skourti-Stathaki K, Ventz S, Pinello L, Yen A, Kamieniarz-Gdula K, Dimitrov S, Pathania S, McKinney KM, Eaton ML et al (2015) BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol Cell 57:636–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hecht F (1988) Rare and polymorphic fragile sites and cancer. Cancer Genet Cytogenet 34:195–199

    Article  CAS  PubMed  Google Scholar 

  • Hedglin M, Zhang Y, O'Brien PJ (2015) Probing the DNA structural requirements for facilitated diffusion. Biochemistry 54:557–566

    Article  CAS  PubMed  Google Scholar 

  • Heitz D, Rousseau F, Devys D, Saccone S, Abderrahim H, Le Paslier D, Cohen D, Vincent A, Toniolo D, Della Valle G et al (1991) Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science 251:1236–1239

    Article  CAS  PubMed  Google Scholar 

  • Hellman A, Rahat A, Scherer SW, Darvasi A, Tsui LC, Kerem B (2000) Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability. Mol Cell Biol 20:4420–4427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Helmrich A, Ballarino M, Tora L (2011) Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 44:966–977

    Article  CAS  PubMed  Google Scholar 

  • Helmrich U, Marsano A, Melly L, Wolff T, Christ L, Heberer M, Scherberich A, Martin I, Banfi A (2012) Generation of human adult mesenchymal stromal/stem cells expressing defined xenogenic vascular endothelial growth factor levels by optimized transduction and flow cytometry purification. Tissue Eng Part C Methods 18:283–292

    Article  CAS  PubMed  Google Scholar 

  • Hill A, Harada Y, Takahashi E, Hou J, Wagner MJ, Wells DE (1997) Assignment of fragile site 8E (FRA8E) to human chromosome band 8q24.11 adjacent to the hereditary multiple exostoses 1 gene and two overlapping Langer-Giedion syndrome deletion endpoints. Cytogenet Cell Genet 78:56–57

    Article  CAS  PubMed  Google Scholar 

  • Hills LB, Masri A, Konno K, Kakegawa W, Lam AT, Lim-Melia E, Chandy N, Hill RS, Partlow JN, Al-Saffar M et al (2013) Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology 81:1378–1386

    Article  PubMed  PubMed Central  Google Scholar 

  • Hoffman EA, McCulley A, Haarer B, Arnak R, Feng W (2015) Break-seq reveals hydroxyurea-induced chromosome fragility as a result of unscheduled conflict between DNA replication and transcription. Genome Res 25:402–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holden JJ, Walker M, Chalifoux M, White BN (1996) Trinucleotide repeats at the FRAXF locus: frequency and distribution in the general population. Am J Med Genet 64:424–427

    Article  CAS  PubMed  Google Scholar 

  • Hormozian F, Schmitt JG, Sagulenko E, Schwab M, Savelyeva L (2007) FRA1E common fragile site breaks map within a 370kilobase pair region and disrupt the dihydropyrimidine dehydrogenase gene (DPYD). Cancer Lett 246:82–91

    Article  CAS  PubMed  Google Scholar 

  • Hosseini SA, Horton S, Saldivar JC, Miuma S, Stampfer MR, Heerema NA, Huebner K (2013) Common chromosome fragile sites in human and murine epithelial cells and FHIT/FRA3B loss-induced global genome instability. Genes Chromosom Cancer 52:1017–1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou S, Du L, Lei B, Pang CP, Zhang M, Zhuang W, Zhang M, Huang L, Gong B, Wang M et al (2014) Genome-wide association analysis of Vogt-Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3. Nat Genet 46:1007–1011

    Article  CAS  PubMed  Google Scholar 

  • Howell RT, McDermott A, Evans JL (1990) A new apparently folate sensitive fragile site, 5q35. J Med Genet 27:527–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu TC (1963) Longitudinal differentiation of chromosomes and the possibility of interstitial telomeres. Exp Cell Res 24(SUPPL9):73–85

    Article  Google Scholar 

  • Hsu YY, Wang YH (2002) Human fragile site FRA16B DNA excludes nucleosomes in the presence of distamycin. J Biol Chem 277:17315–17319

    Article  CAS  PubMed  Google Scholar 

  • Huertas P, Aguilera A (2003) Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12:711–721

    Article  CAS  PubMed  Google Scholar 

  • Ijdo JW, Wells RA, Baldini A, Reeders ST (1991) Improved telomere detection using a telomere repeat probe (TTAGGG)n generated by PCR. Nucleic Acids Res 19:4780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janiszewska-Olszowska J, Gawrych E, Dydyk A, Studniak E, Biadun-Poplawska A, Zajaczek S (2013) Oro-palatal dysplasia Bettex-Graf – clinical findings, genetic background, treatment. J Craniomaxillofac Surg 41:e29–e32

    Article  PubMed  Google Scholar 

  • Jones C, Slijepcevic P, Marsh S, Baker E, Langdon WY, Richards RI, Tunnacliffe A (1994) Physical linkage of the fragile site FRA11B and a Jacobsen syndrome chromosome deletion breakpoint in 11q23.3. Hum Mol Genet 3:2123–2130

    Article  CAS  PubMed  Google Scholar 

  • Jones C, Penny L, Mattina T, Yu S, Baker E, Voullaire L, Langdon WY, Sutherland GR, Richards RI, Tunnacliffe A (1995) Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 376:145–149

    Article  CAS  PubMed  Google Scholar 

  • Kahkonen M, Leisti J, Thoden CJ, Autio S (1986) Frequency of rare fragile sites among mentally subnormal schoolchildren. Clin Genet 30:234–238

    Article  CAS  PubMed  Google Scholar 

  • Kähkönen M, Tengstrom C, Alitalo T, Matilainen R, Kaski M, Airaksinen E (1989) Population cytogenetics of folate-sensitive fragile sites. II. Autosomal rare fragile sites. Hum Genet 82:3–8

    Article  PubMed  Google Scholar 

  • Kang S, Ohshima K, Shimizu M, Amirhaeri S, Wells RD (1995) Pausing of DNA synthesis in vitro at specific loci in CTG and CGG triplet repeats from human hereditary disease genes. J Biol Chem 270:27014–27021

    Article  CAS  PubMed  Google Scholar 

  • Kao-Shan CS, Fine RL, Whang-Peng J, Lee EC, Chabner BA (1987) Increased fragile sites and sister chromatid exchanges in bone marrow and peripheral blood of young cigarette smokers. Cancer Res 47:6278–6282

    CAS  PubMed  Google Scholar 

  • Karayianni E, Magnanini C, Orphanos V, Negrini M, Maniatis GM, Spathas DH, Barbanti-Brodano G, Morelli C (1999) Transcriptional map of chromosome region 6q16 – >q21. Cytogenet Cell Genet 86:263–266

    Article  CAS  PubMed  Google Scholar 

  • Karkera JD, Ayache S, Ransome RJ Jr, Jackson MA, Elsayem AF, Sridhar R, Detera-Wadleigh SD, Wadleigh RG (2000) Refinement of regions with allelic loss on chromosome 18p11.2 and 18q12.2 in esophageal squamous cell carcinoma. Clin Cancer Res 6:3565–3569

    CAS  PubMed  Google Scholar 

  • Kasi Loknath Kumar A, Weckbaugh B, Sirridge C, Woodroof J, Persons D, Kambhampati S (2016) Myelodysplastic syndrome with concomitant t(5;21)(q15;q22) and del(5)(q13q33): case report and review of literature. Stem Cell Inv 3:3

    Google Scholar 

  • Kerbeshian J, Severud R, Burd L, Larson L (2000) Peek-a-boo fragile site at 16d associated with Tourette syndrome, bipolar disorder, autistic disorder, and mental retardation. Am J Med Genet 96:69–73

    Article  CAS  PubMed  Google Scholar 

  • Kerner B (2014) Genetics of bipolar disorder. Appl Clin Genet 7:33–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koch CM, Andrews RM, Flicek P, Dillon SC, Karaoz U, Clelland GK, Wilcox S, Beare DM, Fowler JC, Couttet P et al (2007) The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res 17:691–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252:1711–1714

    Article  CAS  PubMed  Google Scholar 

  • Kuwano A, Murano I, Kajii T (1990) Cell type-dependent difference in the distribution and frequency of excess thymidine-induced common fragile sites: T lymphocytes and skin fibroblasts. Hum Genet 84:527–531

    Article  CAS  PubMed  Google Scholar 

  • Lai LA, Kostadinov R, Barrett MT, Peiffer DA, Pokholok D, Odze R, Sanchez CA, Maley CC, Reid BJ, Gunderson KL et al (2010) Deletion at fragile sites is a common and early event in Barrett’s esophagus. Mol Cancer Res 8:1084–1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Beau MM, Rassool FV, Neilly ME, Espinosa R 3rd, Glover TW, Smith DI, McKeithan TW (1998) Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Hum Mol Genet 7:755–761

    Article  PubMed  Google Scholar 

  • Le Tallec B, Millot GA, Blin ME, Brison O, Dutrillaux B, Debatisse M (2013) Common fragile site profiling in epithelial and erythroid cells reveals that most recurrent cancer deletions lie in fragile sites hosting large genes. Cell Rep 4:420–428

    Article  PubMed  CAS  Google Scholar 

  • Le Tallec B, Koundrioukoff S, Wilhelm T, Letessier A, Brison O, Debatisse M (2014) Updating the mechanisms of common fragile site instability: how to reconcile the different views? Cell Mol Life Sci 71:4489–4494

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee DY, Clayton DA (1996) Properties of a primer RNA-DNA hybrid at the mouse mitochondrial DNA leading-strand origin of replication. J Biol Chem 271:24262–24269

    Article  CAS  PubMed  Google Scholar 

  • Lejeune J, Dutrillaux B, Lafourcade J, Berger R, Abonyi D, Rethore MO (1968) Selective endoreduplication of the long arm of the 2 chromosome in a woman and her daughter. C R Acad Sci Hebd Seances Acad Sci D 266:24–26

    CAS  PubMed  Google Scholar 

  • Letessier A, Garrido-Urbani S, Ginestier C, Fournier G, Esterni B, Monville F, Adelaide J, Geneix J, Xerri L, Dubreuil P et al (2007) Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer. Oncogene 26:298–307

    Article  CAS  PubMed  Google Scholar 

  • Letessier A, Millot GA, Koundrioukoff S, Lachages AM, Vogt N, Hansen RS, Malfoy B, Brison O, Debatisse M (2011) Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. Nature 470:120–123

    Article  CAS  PubMed  Google Scholar 

  • Li X, Manley JL (2005) Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122:365–378

    Article  CAS  PubMed  Google Scholar 

  • Li J, Liu J, Ren Y, Yang J, Liu P (2014) Common chromosomal fragile site gene WWOX in metabolic disorders and tumors. Int J Biol Sci 10:142–148

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li QS, Parrado AR, Samtani MN, Narayan VA, Alzheimer’s Disease Neuroimaging, I (2015) Variations in the FRA10AC1 fragile site and 15q21 are associated with cerebrospinal fluid Abeta1-42 level. PLoS One 10:e0134000

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ligsay A, Hagerman RJ (2016) Review of targeted treatments in fragile X syndrome. Intractable Rare Dis Res 5:158–167

    Article  PubMed  PubMed Central  Google Scholar 

  • Limon J, Dal Cin P, Sait SN, Karakousis C, Sandberg AA (1988) Chromosome changes in metastatic human melanoma. Cancer Genet Cytogenet 30:201–211

    Article  CAS  PubMed  Google Scholar 

  • Lin YJ, Liu X, Chang JS, Chien WK, Chen JH, Tsang H, Hung CH, Lin TH, Huang SM, Liao CC et al (2014) Coronary artery aneurysms occurrence risk analysis between Kawasaki disease and LRP1B gene in Taiwanese children. Biomedicine 4:10

    Article  PubMed  PubMed Central  Google Scholar 

  • Lindsay S, Splitt M, Edney S, Berney TP, Knight SJ, Davies KE, O’Brien O, Gale M, Burn J (1996) PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28. Am J Hum Genet 58:1120–1126

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lipska BS, Koczkowska M, Wierzba J, Ploszynska A, Iliszko M, Izycka-Swieszewska E, Adamkiewicz-Drozynska E, Limon J (2013) On the significance of germline cytogenetic rearrangements at MYCN locus in neuroblastoma. Mol Cytogenet 6:43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu N, Yan J, Chen X, Song J, Wang B, Yao Y (2014) Prenatal diagnosis of a de novo interstitial deletion of 11q (11q22.3 –> q23.3) associated with abnormal ultrasound findings by array comparative genomic hybridization. Mol Cytogenet 7:62

    Article  PubMed  PubMed Central  Google Scholar 

  • Lombrana R, Almeida R, Alvarez A, Gomez M (2015) R-loops and initiation of DNA replication in human cells: a missing link? Front Genet 6:158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lozano R, Azarang A, Wilaisakditipakorn T, Hagerman RJ (2016) Fragile X syndrome: a review of clinical management. Intractable Rare Dis Res 5:145–157

    Article  PubMed  PubMed Central  Google Scholar 

  • Lubs HA (1969) A marker X chromosome. Am J Hum Genet 21:231–244

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lukusa T, Fryns JP (2008) Human chromosome fragility. Biochim Biophys Acta 1779:3–16

    Article  CAS  PubMed  Google Scholar 

  • Ma K, Qiu L, Mrasek K, Zhang J, Liehr T, Quintana LG, Li Z (2012) Common fragile sites: genomic hotspots of DNA damage and carcinogenesis. Int J Mol Sci 13:11974–11999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madireddy A, Kosiyatrakul ST, Boisvert RA, Herrera-Moyano E, Garcia-Rubio ML, Gerhardt J, Vuono EA, Owen N, Yan Z, Olson S et al (2016) FANCD2 facilitates replication through common fragile sites. Mol Cell 64:388–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Magenis RE, Hecht F, Lovrien EW (1970) Heritable fragile site on chromosome 16: probable localization of haptoglobin locus in man. Science 170:85–87

    Article  CAS  PubMed  Google Scholar 

  • Maltby EL, Higgins S (1987) Folate sensitive site at 10q23 and its expression as a deletion. J Med Genet 24:299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martorell MR, Martinez-Pasarell O, Lopez O, Polo A, Sandalinas M, Garcia-Guixe E, Bassas L (2014) Chromosome 16 abnormalities in embryos and in sperm from a male with a fragile site at 16q22.1. Cytogenet Genome Res 142:134–139

    Article  CAS  PubMed  Google Scholar 

  • McAvoy S, Zhu Y, Perez DS, James CD, Smith DI (2008) Disabled-1 is a large common fragile site gene, inactivated in multiple cancers. Genes Chromosom Cancer 47:165–174

    Article  CAS  PubMed  Google Scholar 

  • McKenzie F, Turner A, Withers S, Dalzell P, McGlynn M, Kirk EP (2002) Dominant inheritance of cleft palate, microstomia and micrognathia–possible linkage to the fragile site at 16q22 (FRA16B). Clin Dysmorphol 11:237–241

    Article  CAS  PubMed  Google Scholar 

  • Metsu S, Rooms L, Rainger J, Taylor MS, Bengani H, Wilson DI, Chilamakuri CS, Morrison H, Vandeweyer G, Reyniers E et al (2014a) FRA2A is a CGG repeat expansion associated with silencing of AFF3. PLoS Genet 10:e1004242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Metsu S, Rainger JK, Debacker K, Bernhard B, Rooms L, Grafodatskaya D, Weksberg R, Fombonne E, Taylor MS, Scherer SW et al (2014b) A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families. Hum Mutat 35:1295–1300

    CAS  PubMed  Google Scholar 

  • Michaelis RC, Velagaleti GV, Jones C, Pivnick EK, Phelan MC, Boyd E, Tarleton J, Wilroy RS, Tunnacliffe A, Tharapel AT (1998) Most Jacobsen syndrome deletion breakpoints occur distal to FRA11B. Am J Med Genet 76:222–228

    Article  CAS  PubMed  Google Scholar 

  • Miles JH (2011) Autism spectrum disorders–a genetics review. Genet Med 13:278–294

    Article  PubMed  Google Scholar 

  • Mirkin SM (2006) DNA structures, repeat expansions and human hereditary disorders. Curr Opin Struct Biol 16:351–358

    Article  CAS  PubMed  Google Scholar 

  • Mishmar D, Rahat A, Scherer SW, Nyakatura G, Hinzmann B, Kohwi Y, Mandel-Gutfroind Y, Lee JR, Drescher B, Sas DE et al (1998) Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site. Proc Natl Acad Sci U S A 95:8141–8146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schols L et al (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 36:225–227

    Article  CAS  PubMed  Google Scholar 

  • Morelli C, Karayianni E, Magnanini C, Mungall AJ, Thorland E, Negrini M, Smith DI, Barbanti-Brodano G (2002) Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene 21:7266–7276

    Article  CAS  PubMed  Google Scholar 

  • Moriarty HT, Webster LR (2003) Fragile sites and bladder cancer. Cancer Genet Cytogenet 140:89–98

    Article  CAS  PubMed  Google Scholar 

  • Mrasek K, Schoder C, Teichmann AC, Behr K, Franze B, Wilhelm K, Blaurock N, Claussen U, Liehr T, Weise A (2010) Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones. Int J Oncol 36:929–940

    PubMed  Google Scholar 

  • Mulatinho MV, de Carvalho Serao CL, Scalco F, Hardekopf D, Pekova S, Mrasek K, Liehr T, Weise A, Rao N, Llerena JC Jr (2012) Severe intellectual disability, omphalocele, hypospadia and high blood pressure associated to a deletion at 2q22.1q22.3: case report. Mol Cytogenet 5:30

    Article  PubMed  PubMed Central  Google Scholar 

  • Murano I, Kuwano A, Kajii T (1989a) Fibroblast-specific common fragile sites induced by aphidicolin. Hum Genet 83:45–48

    Article  CAS  PubMed  Google Scholar 

  • Murano I, Kuwano A, Kajii T (1989b) Cell type-dependent difference in the distribution and frequency of aphidicolin-induced fragile sites: T and B lymphocytes and bone marrow cells. Hum Genet 84:71–74

    Article  CAS  PubMed  Google Scholar 

  • Nadel J, Athanasiadou R, Lemetre C, Wijetunga NA, O Broin P, Sato H, Zhang Z, Jeddeloh J, Montagna C, Golden A et al (2015) RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships. Epigenetics Chromatin 8:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nikitina NV, Bushueva OA, Nikolaeva EB, Pavlov GV, Lurie IW (2003) Maternal transmission of a ring chromosome 15. Genet Couns 14:181–186

    CAS  PubMed  Google Scholar 

  • Oei L, Hsu YH, Styrkarsdottir U, Eussen BH, de Klein A, Peters MJ, Halldorsson B, Liu CT, Alonso N, Kaptoge SK et al (2014) A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. J Med Genet 51:122–131

    Article  PubMed  Google Scholar 

  • Olavesen MG, Davies AF, Broxholme SJ, Wixon JL, Senger G, Nizetic D, Campbell RD, Ragoussis J (1995) An integrated map of human chromosome 6p23. Genome Res 5:342–358

    Article  CAS  PubMed  Google Scholar 

  • Ozeri-Galai E, Lebofsky R, Rahat A, Bester AC, Bensimon A, Kerem B (2011) Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites. Mol Cell 43:122–131

    Article  CAS  PubMed  Google Scholar 

  • Ozeri-Galai E, Tur-Sinai M, Bester AC, Kerem B (2014) Interplay between genetic and epigenetic factors governs common fragile site instability in cancer. Cell Mol Life Sci 71:4495–4506

    Article  CAS  PubMed  Google Scholar 

  • Palakodeti A, Han Y, Jiang Y, Le Beau MM (2004) The role of late/slow replication of the FRA16D in common fragile site induction. Genes Chromosom Cancer 39:71–76

    Article  CAS  PubMed  Google Scholar 

  • Palumbo E, Matricardi L, Tosoni E, Bensimon A, Russo A (2010) Replication dynamics at common fragile site FRA6E. Chromosoma 119:575–587

    Article  CAS  PubMed  Google Scholar 

  • Pangeni RP, Channathodiyil P, Huen DS, Eagles LW, Johal BK, Pasha D, Hadjistephanou N, Nevell O, Davies CL, Adewumi AI et al (2015) The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain. Clin Epigenetics 7:57

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pelliccia F, Bosco N, Curatolo A, Rocchi A (2008) Replication timing of two human common fragile sites: FRA1H and FRA2G. Cytogenet Genome Res 121:196–200

    Article  CAS  PubMed  Google Scholar 

  • Pelliccia F, Bosco N, Rocchi A (2010) Breakages at common fragile sites set boundaries of amplified regions in two leukemia cell lines K562 – molecular characterization of FRA2H and localization of a new CFS FRA2S. Cancer Lett 299:37–44

    Article  CAS  PubMed  Google Scholar 

  • Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66:817–822

    Article  CAS  PubMed  Google Scholar 

  • Plaja A, Castells N, Cueto-Gonzalez AM, del Campo M, Vendrell T, Lloveras E, Izquierdo L, Borregan M, Rodriguez-Santiago B, Carrio A et al (2015) A novel recurrent breakpoint responsible for rearrangements in the Williams-Beuren region. Cytogenet Genome Res 146:181–186

    Article  CAS  PubMed  Google Scholar 

  • Rader JS, Kamarasova T, Huettner PC, Li L, Li Y, Gerhard DS (1996) Allelotyping of all chromosomal arms in invasive cervical cancer. Oncogene 13:2737–2741

    CAS  PubMed  Google Scholar 

  • Reidy JA (1987) Folate- and deoxyuridine-sensitive chromatid breakage may result from DNA repair during G2. Mutat Res 192:217–219

    Article  CAS  PubMed  Google Scholar 

  • Reshmi SC, Huang X, Schoppy DW, Black RC, Saunders WS, Smith DI, Gollin SM (2007) Relationship between FRA11F and 11q13 gene amplification in oral cancer. Genes Chromosom Cancer 46:143–154

    Article  CAS  PubMed  Google Scholar 

  • Rinaldi A, Capello D, Scandurra M, Greiner TC, Chan WC, Bhagat G, Rossi D, Morra E, Paulli M, Rambaldi A et al (2010) Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma. Br J Haematol 149:569–577

    Article  CAS  PubMed  Google Scholar 

  • Rodenas-Cuadrado P, Ho J, Vernes SC (2014) Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet 22:171–178

    Article  CAS  PubMed  Google Scholar 

  • Roy D, Lieber MR (2009) G clustering is important for the initiation of transcription-induced R-loops in vitro, whereas high G density without clustering is sufficient thereafter. Mol Cell Biol 29:3124–3133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saldivar JC, Shibata H, Huebner K (2010) Pathology and biology associated with the fragile FHIT gene and gene product. J Cell Biochem 109:858–865

    CAS  PubMed  Google Scholar 

  • Samadashwily GM, Raca G, Mirkin SM (1997) Trinucleotide repeats affect DNA replication in vivo. Nat Genet 17:298–304

    Article  CAS  PubMed  Google Scholar 

  • Santoro MR, Bray SM, Warren ST (2012) Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol 7:219–245

    Article  CAS  PubMed  Google Scholar 

  • Santos-Pereira JM, Aguilera A (2015) R loops: new modulators of genome dynamics and function. Nat Rev Genet 16:583–597

    Article  CAS  PubMed  Google Scholar 

  • Sanz LA, Hartono SR, Lim YW, Steyaert S, Rajpurkar A, Ginno PA, Xu X, Chedin F (2016) Prevalent, dynamic, and conserved R-loop structures associate with specific epigenomic signatures in mammals. Mol Cell 63:167–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarni D, Kerem B (2016) The complex nature of fragile site plasticity and its importance in cancer. Curr Opin Cell Biol 40:131–136

    Article  CAS  PubMed  Google Scholar 

  • Savelyeva L, Brueckner LM (2014) Molecular characterization of common fragile sites as a strategy to discover cancer susceptibility genes. Cell Mol Life Sci 71:4561–4575

    Article  CAS  PubMed  Google Scholar 

  • Savelyeva L, Sagulenko E, Schmitt JG, Schwab M (2006a) Low-frequency common fragile sites: link to neuropsychiatric disorders? Cancer Lett 232:58–69

    Article  CAS  PubMed  Google Scholar 

  • Savelyeva L, Sagulenko E, Schmitt JG, Schwab M (2006b) The neurobeachin gene spans the common fragile site FRA13A. Hum Genet 118:551–558

    Article  CAS  PubMed  Google Scholar 

  • Schmid M, Feichtinger W, Jessberger A, Kohler J, Lange R (1986) The fragile site (16) (q22). I. Induction by AT-specific DNA-ligands and population frequency. Hum Genet 74:67–73

    CAS  PubMed  Google Scholar 

  • Schneider B, Nagel S, Kaufmann M, Winkelmann S, Bode J, Drexler HG, MacLeod RA (2008) T(3;7)(q27;q32) fuses BCL6 to a non-coding region at FRA7H near miR-29. Leukemia 22:1262–1266

    Article  CAS  PubMed  Google Scholar 

  • Schonhoft JD, Kosowicz JG, Stivers JT (2013) DNA translocation by human uracil DNA glycosylase: role of DNA phosphate charge. Biochemistry 52:2526–2535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwartz M, Zlotorynski E, Kerem B (2006) The molecular basis of common and rare fragile sites. Cancer Lett 232:13–26

    Article  CAS  PubMed  Google Scholar 

  • Seki N, Sumiya H, Shimazaki J, Toyama Y, Takahashi E, Murata M, Hori T (1992) Chromosome abnormalities and rare fragile sites detected in azoospermia patients. Jpn J Hum Genet 37:215–222

    Article  CAS  PubMed  Google Scholar 

  • Shabtai F, Klar D, Halbrecht I (1982) Chromosome 17 has a real fragile site at p12. Hum Genet 61:177–179

    Article  CAS  PubMed  Google Scholar 

  • Shang Z, Lv H, Zhang M, Duan L, Wang S, Li J, Liu G, Ruijie Z, Jiang Y (2015) Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals. Oncotarget 6:42504–42514

    PubMed  PubMed Central  Google Scholar 

  • Sherman SL, Sutherland GR (1986) Segregation analysis of rare autosomal fragile sites. Hum Genet 72:123–128

    Article  CAS  PubMed  Google Scholar 

  • Shiraishi Y, Li MJ (1993) Uncorrected SCE levels of Bloom syndrome cells by cell hybridization with malignant cells with 14q32 structural abnormalities. Cancer Genet Cytogenet 69:45–50

    Article  CAS  PubMed  Google Scholar 

  • Simmers RN, Stupans I, Sutherland GR (1986) Localization of the human haptoglobin genes distal to the fragile site at 16q22 using in situ hybridization. Cytogenet Cell Genet 41:38–41

    Article  CAS  PubMed  Google Scholar 

  • Skourti-Stathaki K, Proudfoot NJ, Gromak N (2011) Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42:794–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith CL, Bolton A, Nguyen G (2010) Genomic and epigenomic instability, fragile sites, schizophrenia and autism. Curr Genomics 11:447–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sordet O, Redon CE, Guirouilh-Barbat J, Smith S, Solier S, Douarre C, Conti C, Nakamura AJ, Das BB, Nicolas E et al (2009) Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks. EMBO Rep 10:887–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sotiriou SK, Kamileri I, Lugli N, Evangelou K, Da-Re C, Huber F, Padayachy L, Tardy S, Nicati NL, Barriot S et al (2016) Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks. Mol Cell 64:1127–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian PS, Nelson DL, Chinault AC (1996) Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE. Am J Hum Genet 59:407–416

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sugimoto N, Nakano S, Katoh M, Matsumura A, Nakamuta H, Ohmichi T, Yoneyama M, Sasaki M (1995) Thermodynamic parameters to predict stability of RNA/DNA hybrid duplexes. Biochemistry 34:11211–11216

    Article  CAS  PubMed  Google Scholar 

  • Sutherland GR (1977) Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture medium. Science 197:265–266

    Article  CAS  PubMed  Google Scholar 

  • Sutherland GR (1979) Heritable fragile sites on human chromosomes I. Factors affecting expression in lymphocyte culture. Am J Hum Genet 31:125–135

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sutherland GR (1981) Heritable fragile sites on human chromosomes. VII. Children homozygous for the BrdU-requiring fra(10)(q25) are phenotypically normal. Am J Hum Genet 33:946–949

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sutherland GR (1991) Chromosomal fragile sites. Genet Anal Tech Appl 8:161–166

    Article  CAS  PubMed  Google Scholar 

  • Sutherland GR, Baker E (1993) Unusual behaviour of a human autosome having two rare folate sensitive fragile sites. Ann Genet 36:159–162

    CAS  PubMed  Google Scholar 

  • Sutherland GR, Baker E (2003) Forgotten fragile sites and related phenomena. Cytogenet Genome Res 100:89–91

    Article  CAS  PubMed  Google Scholar 

  • Tassano E, Tavella E, Micalizzi C, Panarello C, Morerio C (2010) Refractory cytopenia of childhood with monosomy 7 presenting as isolated neutropenia in a patient with fragile site at 16q22. Cancer Genet Cytogenet 201:70–71

    Article  CAS  PubMed  Google Scholar 

  • Tatarelli C, Linnenbach A, Mimori K, Croce CM (2000) Characterization of the human TESTIN gene localized in the FRA7G region at 7q31.2. Genomics 68:1–12

    Article  CAS  PubMed  Google Scholar 

  • Tchurikov NA, Kretova OV, Fedoseeva DM, Chechetkin VR, Gorbacheva MA, Snezhkina AV, Alembekov IR, Kravatskaya GI, Kravatsky YV (2015) Genome-wide mapping of hot spots of DNA double-strand breaks in human cells as a tool for epigenetic studies and cancer genomics. Genomics Data 5:89–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorland EC, Myers SL, Persing DH, Sarkar G, McGovern RM, Gostout BS, Smith DI (2000) Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res 60:5916–5921

    CAS  PubMed  Google Scholar 

  • Thys RG, Lehman CE, Pierce LC, Wang YH (2015) DNA secondary structure at chromosomal fragile sites in human disease. Curr Genomics 16:60–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tracy RB, Hsieh CL, Lieber MR (2000) Stable RNA/DNA hybrids in the mammalian genome: inducible intermediates in immunoglobulin class switch recombination. Science 288:1058–1061

    Article  CAS  PubMed  Google Scholar 

  • Tunca B, Egeli U, Zorluoglu A, Yilmazlar T, Yerci O, Kizil A (2000) The expression of fragile sites in lymphocytes of patients with rectum cancer and their first-degree relatives. Cancer Lett 152:201–209

    Article  CAS  PubMed  Google Scholar 

  • Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S et al (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 28:1248–1250

    Article  CAS  PubMed  Google Scholar 

  • Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E et al (2013) FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet 92:990–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Usdin K, Woodford KJ (1995) CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro. Nucleic Acids Res 23:4202–4209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Usdin K, Hayward BE, Kumari D, Lokanga RA, Sciascia N, Zhao XN (2014) Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders. Front Genet 5:226

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Schil K, Meire F, Karlstetter M, Bauwens M, Verdin H, Coppieters F, Scheiffert E, Van Nechel C, Langmann T, Deconinck N et al (2015) Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion. Genet Med 17:291–299

    Article  PubMed  CAS  Google Scholar 

  • Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914

    Article  CAS  PubMed  Google Scholar 

  • Vianna-Morgante AM, Mingroni-Netto RC, Barbosa AC, Otto PA, Rosenberg C (1996) FRAXF in a patient with chromosome 8 duplication. J Med Genet 33:611–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voiculescu I, Back E, Schempp W (1991) Homozygous condition for a BrdU-requiring fragile site on chromosome 12. Hum Genet 86:416–417

    Article  CAS  PubMed  Google Scholar 

  • Wang YH, Griffith J (1996) Methylation of expanded CCG triplet repeat DNA from fragile X syndrome patients enhances nucleosome exclusion. J Biol Chem 271:22937–22940

    Article  CAS  PubMed  Google Scholar 

  • Wang YH, Gellibolian R, Shimizu M, Wells RD, Griffith J (1996) Long CCG triplet repeat blocks exclude nucleosomes: a possible mechanism for the nature of fragile sites in chromosomes. J Mol Biol 263:511–516

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Darling J, Zhang JS, Huang H, Liu W, Smith DI (1999) Allele-specific late replication and fragility of the most active common fragile site, FRA3B. Hum Mol Genet 8:431–437

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Bray SM, Warren ST (2012) New perspectives on the biology of fragile X syndrome. Curr Opin Genet Dev 22:256–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Webb T (1992) Delayed replication of Xq27 in individuals with the fragile X syndrome. Am J Med Genet 43:1057–1062

    Article  CAS  PubMed  Google Scholar 

  • Webb T, Thake A (1984) Fragile 22q13 segregating in a family. Clin Genet 26:125–128

    Article  CAS  PubMed  Google Scholar 

  • Widrow RJ, Hansen RS, Kawame H, Gartler SM, Laird CD (1998) Very late DNA replication in the human cell cycle. Proc Natl Acad Sci U S A 95:11246–11250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson TE, Arlt MF, Park SH, Rajendran S, Paulsen M, Ljungman M, Glover TW (2015) Large transcription units unify copy number variants and common fragile sites arising under replication stress. Genome Res 25:189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winnepenninckx B, Debacker K, Ramsay J, Smeets D, Smits A, FitzPatrick DR, Kooy RF (2007) CGG-repeat expansion in the DIP2B gene is associated with the fragile site FRA12A on chromosome 12q13.1. Am J Hum Genet 80:221–231

    Article  CAS  PubMed  Google Scholar 

  • Wongsurawat T, Jenjaroenpun P, Kwoh CK, Kuznetsov V (2012) Quantitative model of R-loop forming structures reveals a novel level of RNA-DNA interactome complexity. Nucleic Acids Res 40:e16

    Article  CAS  PubMed  Google Scholar 

  • Xia JH, Li LY, He XX, Xiao JY (1988) Fragile site 1q44 involved in nasopharyngeal carcinoma. A study of a marker chromosome der(1)t(1;3)(q44;p11). Cancer Genet Cytogenet 35:135–140

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Mangelsdorf M, Hewett D, Hobson L, Baker E, Eyre HJ, Lapsys N, Le Paslier D, Doggett NA, Sutherland GR et al (1997) Human chromosomal fragile site FRA16B is an amplified AT-rich minisatellite repeat. Cell 88:367–374

    Article  CAS  PubMed  Google Scholar 

  • Yu K, Chedin F, Hsieh CL, Wilson TE, Lieber MR (2003) R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat Immunol 4:442–451

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Freudenreich CH (2007) An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol Cell 27:367–379

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao, X.N. Usdin, K. (2016) Ups and downs: mechanisms of repeat instability in the fragile X-related disorders. Genes 7

    Google Scholar 

  • Zhu Y, McAvoy S, Kuhn R, Smith DI (2006) RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene 25:2901–2908

    Article  CAS  PubMed  Google Scholar 

  • Zimonjic DB, Durkin ME, Keck-Waggoner CL, Park SW, Thorgeirsson SS, Popescu NC (2003) SMAD5 gene expression, rearrangements, copy number, and amplification at fragile site FRA5C in human hepatocellular carcinoma. Neoplasia 5:390–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlotorynski E, Rahat A, Skaug J, Ben-Porat N, Ozeri E, Hershberg R, Levi A, Scherer SW, Margalit H, Kerem B (2003) Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 23:7143–7151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

We thank Andrew McCulley for assisting data analysis during this work. This work was supported by the National Institutes of Health (5R01 GM118799-01A1 to W.F.).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA

    Wenyi Feng & Arijita Chakraborty

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  1. Wenyi Feng
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  2. Arijita Chakraborty
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Correspondence to Wenyi Feng .

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Editors and Affiliations

  1. Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Hisao Masai

  2. Istituto FIRC di Oncologia Molecolare, Milan, Italy

    Marco Foiani

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Feng, W., Chakraborty, A. (2017). Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites. In: Masai, H., Foiani, M. (eds) DNA Replication. Advances in Experimental Medicine and Biology, vol 1042. Springer, Singapore. https://doi.org/10.1007/978-981-10-6955-0_21

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