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Ribosomal DNA instability and genome adaptability

  • Devika Salim
  • Jennifer L. GertonEmail author
Review

Abstract

Ribosomes are large, multi-subunit ribonucleoprotein complexes, essential for protein synthesis. To meet the high cellular demand for ribosomes, all eukaryotes have numerous copies of ribosomal DNA (rDNA) genes that encode ribosomal RNA (rRNA), usually far in excess of the requirement for ribosome biogenesis. In all eukaryotes studied, rDNA genes are arranged in one or more clusters of tandem repeats localized to nucleoli. The tandem arrangement of repeats, combined with the high rates of transcription at the rDNA loci, and the difficulty of replicating repetitive sequences make the rDNA inherently unstable and particularly susceptible to large variations in repeat copy number. Despite mounting evidence suggesting extra-ribosomal functions of the rDNA, its repetitive nature has excluded it from traditional sequencing-based studies. However, more recently, several studies have revealed the unique potential of the rDNA to act as a “canary in the coalmine,” being particularly sensitive to genomic stresses and acting as a source of adaptive response. Here, we review evidence uncovering mechanisms of regulation of instability and copy number variation at the rDNA and their role in adaptation to the environment, which could serve to understand the basic principles governing the behavior of other tandem repeats and their role in shaping the genome.

Keywords

rDNA Transcription Replication Replication-transcription conflicts Instability Copy number variation Adaptive mutations 

Notes

Acknowledgements

We thank Mark Miller (Stowers Institute) for his help with illustrations. This work was done to fulfill, in part, the requirements for DS’s PhD thesis research as a student registered with the Open University.

Author contributions

DS and JLG wrote, reviewed, and edited the manuscript.

Funding

This work was funded by the Stowers Institute for Medical Research.

References

  1. Aguilera A, Garcia-Muse T (2012) R loops: from transcription byproducts to threats to genome stability. Mol Cell 46:115–124PubMedCrossRefGoogle Scholar
  2. Akamatsu Y, Kobayashi T (2015) The human RNA polymerase I transcription terminator complex acts as a replication fork barrier that coordinates the progress of replication with rRNA transcription activity. Mol Cell Biol 35:1871–1881PubMedPubMedCentralCrossRefGoogle Scholar
  3. Albert B, Leger-Silvestre I, Normand C, Ostermaier MK, Perez-Fernandez J et al (2011) RNA polymerase I-specific subunits promote polymerase clustering to enhance the rRNA gene transcription cycle. J Cell Biol 192:277–293PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bersani F, Lee E, Kharchenko PV, Xu AW, Liu M, Xega K, MacKenzie OC, Brannigan BW, Wittner BS, Jung H, Ramaswamy S, Park PJ, Maheswaran S, Ting DT, Haber DA (2015) Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer. Proc Natl Acad Sci U S A 112:15148–15153PubMedPubMedCentralCrossRefGoogle Scholar
  5. Brahmachary M, Guilmatre A, Quilez J, Hasson D, Borel C, Warburton P, Sharp AJ (2014) Digital genotyping of macrosatellites and multicopy genes reveals novel biological functions associated with copy number variation of large tandem repeats. PLoS Genet 10:e1004418PubMedPubMedCentralCrossRefGoogle Scholar
  6. Brewer BJ, Lockshon D, Fangman WL (1992) The arrest of replication forks in the rDNA of yeast occurs independently of transcription. Cell 71:267–276PubMedCrossRefGoogle Scholar
  7. Cahyani I, Cridge AG, Engelke DR, Ganley AR, O’Sullivan JM (2015) A sequence-specific interaction between the Saccharomyces cerevisiae rRNA gene repeats and a locus encoding an RNA polymerase I subunit affects ribosomal DNA stability. Mol Cell Biol 35:544–554PubMedPubMedCentralCrossRefGoogle Scholar
  8. Carter NP (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nat Genet 39:S16–S21PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chestkov IV, Jestkova EM, Ershova ES, Golimbet VE, Lezheiko TV, Kolesina NY, Porokhovnik LN, Lyapunova NA, Izhevskaya VL, Kutsev SI, Veiko NN, Kostyuk SV (2018) Abundance of ribosomal RNA gene copies in the genomes of schizophrenia patients. Schizophr Res 197:305–314CrossRefGoogle Scholar
  10. Dalgaard JZ, Godfrey EL, MacFarlane RJ (2011) Eukaryotic replication barriers: how, why and where forks stall. DNA Replication-Current Advances. pp 269–304Google Scholar
  11. Diermeier SD, Nemeth A, Rehli M, Grummt I, Langst G (2013) Chromatin-specific regulation of mammalian rDNA transcription by clustered TTF-I binding sites. PLoS Genet 9:e1003786PubMedPubMedCentralCrossRefGoogle Scholar
  12. Diesch J, Hannan RD, Sanij E (2014) Perturbations at the ribosomal genes loci are at the centre of cellular dysfunction and human disease. Cell Biosci 4:43PubMedPubMedCentralCrossRefGoogle Scholar
  13. El Hage A, French SL, Beyer AL, Tollervey D (2010) Loss of topoisomerase I leads to R-loop-mediated transcriptional blocks during ribosomal RNA synthesis. Genes Dev 24:1546–1558PubMedPubMedCentralCrossRefGoogle Scholar
  14. Feng J, Liang J, Li J, Li Y, Liang H, Zhao X, McNutt MA, Yin Y (2015) PTEN controls the DNA replication process through MCM2 in response to replicative stress. Cell Rep 13:1295–1303PubMedCrossRefGoogle Scholar
  15. Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, Alvarez S, Diolaiti ME, Ugarte F, Forsberg EC, le Beau MM, Stohr BA, Méndez J, Morrison CG, Passegué E (2014) Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512:198–202PubMedPubMedCentralCrossRefGoogle Scholar
  16. Forsburg SL, Shen KF (2017) Centromere stability: the replication connection. Genes (Basel) 8Google Scholar
  17. Foss EJ, Lao U, Dalrymple E, Adrianse RL, Loe T, Bedalov A (2017) SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences. Proc Natl Acad Sci U S A 114:552–557PubMedPubMedCentralCrossRefGoogle Scholar
  18. French SL, Osheim YN, Cioci F, Nomura M, Beyer AL (2003) In exponentially growing Saccharomyces cerevisiae cells, rRNA synthesis is determined by the summed RNA polymerase I loading rate rather than by the number of active genes. Mol Cell Biol 23:1558–1568PubMedPubMedCentralCrossRefGoogle Scholar
  19. Gaillard H, Aguilera A (2016) Transcription as a threat to genome integrity. Annu Rev Biochem 85:291–317PubMedCrossRefGoogle Scholar
  20. Garcia-Muse T, Aguilera A (2016) Transcription-replication conflicts: how they occur and how they are resolved. Nat Rev Mol Cell Biol 17:553–563PubMedCrossRefPubMedCentralGoogle Scholar
  21. Gerber J-K, Gögel E, Berger C, Wallisch M, Müller F, Grummt I, Grummt F (1997) Termination of mammalian rDNA replication: polar arrest of replication fork movement by transcription termination factor TTF-I. Cell 90:559–567PubMedCrossRefPubMedCentralGoogle Scholar
  22. Gibbons JG, Branco AT, Yu S, Lemos B (2014) Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans. Nat Commun 5:4850PubMedCrossRefPubMedCentralGoogle Scholar
  23. Gibbons JG, Branco AT, Godinho SA, Yu S, Lemos B (2015) Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes. Proc Natl Acad Sci U S A 112:2485–2490PubMedPubMedCentralCrossRefGoogle Scholar
  24. Ginno PA, Lott PL, Christensen HC, Korf I, Chedin F (2012) R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol Cell 45:814–825PubMedPubMedCentralCrossRefGoogle Scholar
  25. Gonzalez IL, Sylvester JE (1995) Complete sequence of the 43-kb human ribosomal DNA repeat: analysis of the intergenic spacer. Genomics 27:320–328PubMedCrossRefPubMedCentralGoogle Scholar
  26. Gonzalez IL, Sylvester JE (2001) Human rDNA: evolutionary patterns within the genes and tandem arrays derived from multiple chromosomes. Genomics 73:255–263PubMedCrossRefPubMedCentralGoogle Scholar
  27. Hall LE, Mitchell SE, O'Neill RJ (2012) Pericentric and centromeric transcription: a perfect balance required. Chromosom Res 20:535–546CrossRefGoogle Scholar
  28. Hallgren J, Pietrzak M, Rempala G, Nelson PT, Hetman M (2014) Neurodegeneration-associated instability of ribosomal DNA. Biochim Biophys Acta 1842:860–868PubMedPubMedCentralCrossRefGoogle Scholar
  29. Hamperl S, Cimprich KA (2016) Conflict resolution in the genome: how transcription and replication make it work. Cell 167:1455–1467PubMedPubMedCentralCrossRefGoogle Scholar
  30. Hannan RD, Drygin D, Pearson RB (2013) Targeting RNA polymerase I transcription and the nucleolus for cancer therapy. Expert Opin Ther Targets 17:873–878PubMedCrossRefPubMedCentralGoogle Scholar
  31. Henderson AS, Warburton D, Atwood KC (1972) Location of ribosomal DNA in the human chromosome complement. Proc Natl Acad Sci U S A 69:3394–3398PubMedPubMedCentralCrossRefGoogle Scholar
  32. Hernández P, Martín-Parras L, Martínez-Robles ML, Schvartzman JB (1993) Conserved features in the mode of replication of eukaryotic ribosomal RNA genes. EMBO J 12:1475–1485PubMedPubMedCentralCrossRefGoogle Scholar
  33. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, Kitano TK, Hodel MR, Petersen JF, Wyatt PW, Steenblock ER, Shah PH, Bousse LJ, Troup CB, Mellen JC, Wittmann DK, Erndt NG, Cauley TH, Koehler RT, So AP, Dube S, Rose KA, Montesclaros L, Wang S, Stumbo DP, Hodges SP, Romine S, Milanovich FP, White HE, Regan JF, Karlin-Neumann GA, Hindson CM, Saxonov S, Colston BW (2011) High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 83:8604–8610PubMedPubMedCentralCrossRefGoogle Scholar
  34. Hull RM, Cruz C, Jack CV, Houseley J (2017) Environmental change drives accelerated adaptation through stimulated copy number variation. PLoS Biol 15:e2001333PubMedPubMedCentralCrossRefGoogle Scholar
  35. Ide S, Watanabe K, Watanabe H, Shirahige K, Kobayashi T, Maki H (2007) Abnormality in initiation program of DNA replication is monitored by the highly repetitive rRNA gene array on chromosome XII in budding yeast. Mol Cell Biol 27:568–578PubMedCrossRefPubMedCentralGoogle Scholar
  36. Ide S, Miyazaki T, Maki H, Kobayashi T (2010) Abundance of ribosomal RNA gene copies maintains genome integrity. Science 327:693–696PubMedCrossRefPubMedCentralGoogle Scholar
  37. Ide S, Saka K, Kobayashi T (2013) Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast. PLoS Genet 9:e1003410PubMedPubMedCentralCrossRefGoogle Scholar
  38. Jack CV, Cruz C, Hull RM, Keller MA, Ralser M, Houseley J (2015) Regulation of ribosomal DNA amplification by the TOR pathway. Proc Natl Acad Sci U S A 112:9674–9679PubMedPubMedCentralCrossRefGoogle Scholar
  39. Kanellopoulou C, Muljo SA, Kung AL, Ganesan S, Drapkin R et al (2005) Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19:489–501PubMedPubMedCentralCrossRefGoogle Scholar
  40. Kim N, Jinks-Robertson S (2012) Transcription as a source of genome instability. Nat Rev Genet 13:204–214PubMedPubMedCentralCrossRefGoogle Scholar
  41. Kobayashi T (2003) The replication fork barrier site forms a unique structure with Fob1p and inhibits the replication fork. Mol Cell Biol 23:9178–9188PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kobayashi T (2014) Ribosomal RNA gene repeats, their stability and cellular senescence. Proc Jpn Acad Ser B Phys Biol Sci 90:119–129PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kobayashi T, Ganley AR (2005) Recombination regulation by transcription-induced cohesin dissociation in rDNA repeats. Science 309:1581–1584PubMedCrossRefGoogle Scholar
  44. Kobayashi T, Sasaki M (2017) rDNA stability is supported by many “buffer genes”—introduction to the Yeast rDNA Stability Database. FEMS Yeast Res 17Google Scholar
  45. Kobayashi T, Heck DJ, Nomura M, Horiuchi T (1998) Expansion and contraction of ribosomal DNA repeats in Saccharomyces cerevisiae: requirement of replication fork blocking (Fob1) protein and the role of RNA polymerase I. Genes Dev 12:3821–3830PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kobayashi T, Horiuchi T, Tongaonkar P, Vu L, Nomura M (2004) SIR2 regulates recombination between different rDNA repeats, but not recombination within individual rRNA genes in yeast. Cell 117:441–453PubMedCrossRefGoogle Scholar
  47. Kunnev D, Rusiniak ME, Kudla A, Freeland A, Cady GK, Pruitt SC (2010) DNA damage response and tumorigenesis in Mcm2-deficient mice. Oncogene 29:3630–3638PubMedPubMedCentralCrossRefGoogle Scholar
  48. Kwan EX, Foss EJ, Tsuchiyama S, Alvino GM, Kruglyak L, Kaeberlein M, Raghuraman MK, Brewer BJ, Kennedy BK, Bedalov A (2013) A natural polymorphism in rDNA replication origins links origin activation with calorie restriction and lifespan. PLoS Genet 9:e1003329PubMedPubMedCentralCrossRefGoogle Scholar
  49. Laferte A, Favry E, Sentenac A, Riva M, Carles C et al (2006) The transcriptional activity of RNA polymerase I is a key determinant for the level of all ribosome components. Genes Dev 20:2030–2040PubMedPubMedCentralCrossRefGoogle Scholar
  50. Lang KS, Merrikh H (2018) The clash of macromolecular titans: replication-transcription conflicts in bacteria. Annu Rev Microbiol 72:71–88PubMedPubMedCentralCrossRefGoogle Scholar
  51. Little RD, Platt TH, Schildkraut CL (1993) Initiation and termination of DNA replication in human rRNA genes. Mol Cell Biol 13:6600–6613PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lu Y, Chang Q, Zhang Y, Beezhold K, Rojanasakul Y et al (2009) Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3. Cell Cycle 8:2101–2109PubMedCrossRefGoogle Scholar
  53. MacAlpine DM, Zhang Z, Kapler GM (1997) Type I elements mediate replication fork pausing at conserved upstream sites in the Tetrahymena thermophila ribosomal DNA minichromosome. Mol Cell Biol 17:4517–4525PubMedPubMedCentralCrossRefGoogle Scholar
  54. Malinovskaya EM, Ershova ES, Golimbet VE, Porokhovnik LN, Lyapunova NA, Kutsev SI, Veiko NN, Kostyuk SV (2018) Copy number of human ribosomal genes with aging: unchanged mean, but narrowed range and decreased variance in elderly group. Front Genet 9:306PubMedPubMedCentralCrossRefGoogle Scholar
  55. Mao J, Appel B, Schaack J, Sharp S, Yamada H, Söll D (1982) The 5S RNA genes of Schizosaccharomyces pombe. Nucleic Acids Res 10:487–500PubMedPubMedCentralCrossRefGoogle Scholar
  56. Masse E, Phoenix P, Drolet M (1997) DNA topoisomerases regulate R-loop formation during transcription of the rrnB operon in Escherichia coli. J Biol Chem 272:12816–12823PubMedCrossRefGoogle Scholar
  57. Mayan M, Aragon L (2010) Cis-interactions between non-coding ribosomal spacers dependent on RNAP-II separate RNAP-I and RNAP-III transcription domains. Cell Cycle 9:4328–4337PubMedCrossRefGoogle Scholar
  58. Mayer C, Schmitz KM, Li J, Grummt I, Santoro R (2006) Intergenic transcripts regulate the epigenetic state of rRNA genes. Mol Cell 22:351–361PubMedCrossRefGoogle Scholar
  59. McNulty SM, Sullivan BA (2018) Alpha satellite DNA biology: finding function in the recesses of the genome. Chromosom Res 26:115–138CrossRefGoogle Scholar
  60. McStay B (2016) Nucleolar organizer regions: genomic ‘dark matter’ requiring illumination. Genes Dev 30:1598–1610PubMedPubMedCentralCrossRefGoogle Scholar
  61. Merrikh CN, Merrikh H (2018) Gene inversion increases evolvability in bacteria. bioRxiv 293571.  https://doi.org/10.1101/293571
  62. Michel AH, Kornmann B, Dubrana K, Shore D (2005) Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing. Genes Dev 19:1199–1210PubMedPubMedCentralCrossRefGoogle Scholar
  63. Nadel J, Athanasiadou R, Lemetre C, Wijetunga NA, Broin PO et al (2015) RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships. Epigenetics Chromatin 8:46PubMedPubMedCentralCrossRefGoogle Scholar
  64. O’Sullivan JM, Sontam DM, Grierson R, Jones B (2009) Repeated elements coordinate the spatial organization of the yeast genome. Yeast 26:125–138PubMedCrossRefPubMedCentralGoogle Scholar
  65. Oakes M, Nogi Y, Clark MW, Nomura M (1993) Structural alterations of the nucleolus in mutants of Saccharomyces cerevisiae defective in RNA polymerase I. Mol Cell Biol 13:2441–2455PubMedPubMedCentralCrossRefGoogle Scholar
  66. Oakes ML, Siddiqi I, Vu L, Aris J, Nomura M (1999) Transcription factor UAF, expansion and contraction of ribosomal DNA (rDNA) repeats, and RNA polymerase switch in transcription of yeast rDNA. Mol Cell Biol 19:8559–8569PubMedPubMedCentralCrossRefGoogle Scholar
  67. Paredes S, Branco AT, Hartl DL, Maggert KA, Lemos B (2011) Ribosomal DNA deletions modulate genome-wide gene expression: “rDNA-sensitive” genes and natural variation. PLoS Genet 7:e1001376PubMedPubMedCentralCrossRefGoogle Scholar
  68. Paul S, Million-Weaver S, Chattopadhyay S, Sokurenko E, Merrikh H (2013) Accelerated gene evolution through replication-transcription conflicts. Nature 495:512–515PubMedCrossRefPubMedCentralGoogle Scholar
  69. Peter J, De Chiara M, Friedrich A, Yue JX, Pflieger D et al (2018) Genome evolution across 1,011 Saccharomyces cerevisiae isolates. Nature 556:339–344PubMedCrossRefPubMedCentralGoogle Scholar
  70. Petes TD (1979) Meiotic mapping of yeast ribosomal deoxyribonucleic acid on chromosome XII. J Bacteriol 138:185–192PubMedPubMedCentralGoogle Scholar
  71. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454PubMedPubMedCentralCrossRefGoogle Scholar
  72. Rosato M, Kovarik A, Garilleti R, Rossello JA (2016) Conserved organisation of 45S rDNA sites and rDNA gene copy number among major clades of early land plants. PLoS One 11:e0162544PubMedPubMedCentralCrossRefGoogle Scholar
  73. Saiki R, Gelfand D, Stoffel S, Scharf S, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491PubMedCrossRefPubMedCentralGoogle Scholar
  74. Saka K, Takahashi A, Sasaki M, Kobayashi T (2016) More than 10% of yeast genes are related to genome stability and influence cellular senescence via rDNA maintenance. Nucleic Acids Res 44:4211–4221PubMedPubMedCentralCrossRefGoogle Scholar
  75. Salim D, Bradford WD, Freeland A, Cady G, Wang J, Pruitt SC, Gerton JL (2017) DNA replication stress restricts ribosomal DNA copy number. PLoS Genet 13:e1007006PubMedPubMedCentralCrossRefGoogle Scholar
  76. Sanchez JA, Kim SM, Huberman JA (1998) Ribosomal DNA replication in the fission yeast, Schizosaccharomyces pombe. Exp Cell Res 238:220–230PubMedCrossRefGoogle Scholar
  77. Sanchez-Gorostiaga A, Lopez-Estrano C, Krimer DB, Schvartzman JB, Hernandez P (2003) Transcription termination factor reb1p causes two replication fork barriers at its cognate sites in fission yeast ribosomal DNA in vivo. Mol Cell Biol 24:398–406CrossRefGoogle Scholar
  78. Sankar TS, Wastuwidyaningtyas BD, Dong Y, Lewis SA, Wang JD (2016) The nature of mutations induced by replication-transcription collisions. Nature 535:178–181PubMedPubMedCentralCrossRefGoogle Scholar
  79. Santoro R, Schmitz KM, Sandoval J, Grummt I (2010) Intergenic transcripts originating from a subclass of ribosomal DNA repeats silence ribosomal RNA genes in trans. EMBO Rep 11:52–58PubMedCrossRefGoogle Scholar
  80. Shyian M, Mattarocci S, Albert B, Hafner L, Lezaja A, Costanzo M, Boone C, Shore D (2016) Budding yeast Rif1 controls genome integrity by inhibiting rDNA replication. PLoS Genet 12:e1006414PubMedPubMedCentralCrossRefGoogle Scholar
  81. Skourti-Stathaki K, Proudfoot NJ (2014) A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev 28:1384–1396PubMedPubMedCentralCrossRefGoogle Scholar
  82. Smith JS, Caputo E, Boeke JD (1999) A genetic screen for ribosomal DNA silencing defects identifies multiple DNA replication and chromatin-modulating factors. Mol Cell Biol 19:3184–3197PubMedPubMedCentralCrossRefGoogle Scholar
  83. Stults DM, Killen MW, Pierce HH, Pierce AJ (2008) Genomic architecture and inheritance of human ribosomal RNA gene clusters. Genome Res 18:13–18PubMedPubMedCentralCrossRefGoogle Scholar
  84. Stults DM, Killen MW, Williamson EP, Hourigan JS, Vargas HD, Arnold SM, Moscow JA, Pierce AJ (2009) Human rRNA gene clusters are recombinational hotspots in cancer. Cancer Res 69:9096–9104PubMedCrossRefPubMedCentralGoogle Scholar
  85. Ting DT, Lipson D, Paul S, Brannigan BW, Akhavanfard S, Coffman EJ, Contino G, Deshpande V, Iafrate AJ, Letovsky S, Rivera MN, Bardeesy N, Maheswaran S, Haber DA (2011) Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science 331:593–596PubMedPubMedCentralCrossRefGoogle Scholar
  86. Tsekrekou M, Stratigi K, Chatzinikolaou G (2017) The nucleolus: in genome maintenance and repair. Int J Mol Sci 18Google Scholar
  87. Udugama M, Sanij E, Voon HPJ, Son J, Hii L et al (2018) Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers. Proc Natl Acad Sci U S A 115:4737–4742PubMedPubMedCentralCrossRefGoogle Scholar
  88. Vogelstein B, Kinzler KW (1999) Digital PCR. Proc Natl Acad Sci 96:9236–9241PubMedCrossRefGoogle Scholar
  89. Wang M, Lemos B (2017) Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation. PLoS Genet 13:e1006994PubMedPubMedCentralCrossRefGoogle Scholar
  90. Warburton PE, Hasson D, Guillem F, Lescale C, Jin X, Abrusan G (2008) Analysis of the largest tandemly repeated DNA families in the human genome. BMC Genomics 9:533PubMedPubMedCentralCrossRefGoogle Scholar
  91. Warner JR (1999) The economics of ribosome biosynthesis in yeast. Trends Biochem Sci 24:437–440PubMedCrossRefPubMedCentralGoogle Scholar
  92. Wiesendanger B, Lucchini R, Koller T, Sogo JM (1994) Replication fork barriers in the Xenopus rDNA. Nucleic Acids Res 22:5038–5046PubMedPubMedCentralCrossRefGoogle Scholar
  93. Wood V, Gwilliam R, Rajandream MA, Lyne M, Lyne R et al (2002) The genome sequence of Schizosaccharomyces pombe. Nature 415:871–880PubMedCrossRefPubMedCentralGoogle Scholar
  94. Wyandt H.E., Wilson G.N., Tonk V.S. (2017) Human chromosome variation: heteromorphism,polymorphism and pathogenesis. Springer, Singapore.  https://doi.org/10.1007/978-981-10-3035-2
  95. Xu B, Li H, Perry JM, Singh VP, Unruh J, Yu Z, Zakari M, McDowell W, Li L, Gerton JL (2017) Ribosomal DNA copy number loss and sequence variation in cancer. PLoS Genet 13:e1006771PubMedPubMedCentralCrossRefGoogle Scholar
  96. Yu S, Lemos B (2018) The long-range interaction map of ribosomal DNA arrays. PLoS Genet 14:e1007258PubMedPubMedCentralCrossRefGoogle Scholar
  97. Zafiropoulos A, Tsentelierou E, Linardakis M, Kafatos A, Spandidos DA (2005) Preferential loss of 5S and 28S rDNA genes in human adipose tissue during ageing. Int J Biochem Cell Biol 37:409–415PubMedCrossRefGoogle Scholar
  98. Zaratiegui M, Castel SE, Irvine DV, Kloc A, Ren J, Li F, de Castro E, Marín L, Chang AY, Goto D, Cande WZ, Antequera F, Arcangioli B, Martienssen RA (2011) RNAi promotes heterochromatic silencing through replication-coupled release of RNA Pol II. Nature 479:135–138PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Stowers Institute for Medical ResearchKansas CityUSA
  2. 2.Open UniversityMilton KeynesUK
  3. 3.Department of Biochemistry and Molecular BiologyUniversity of Kansas Medical CenterKansas CityUSA

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