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Genome Instability of Repetitive Sequence: Lesson from the Ribosomal RNA Gene Repeat

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DNA Replication, Recombination, and Repair

Abstract

Chromosomal DNA is not equally stable all over the genome. Some regions, especially those characterized by repetitive sequences, are known to be “fragile sites” where DNA damage occurs more frequently than in other regions. In such regions, DNA replication is inhibited and DNA double-strand breaks are induced. Repetitive sequences easily form DNA secondary structures, and during repair of double-strand breaks, a broken end may recombine with a repeat at the non-original site which results in translocation. The well-studied ribosomal RNA gene repeat (called rDNA) is the largest repetitive region in the eukaryotic genome. In the case of budding yeast, the rDNA occupies ~10 % of the genome. Because of the size and unstable features of rDNA, its stability dominates that of the overall genome and affects cellular functions, such as senescence. In this review, I will introduce the unique mechanisms by which the rDNA repetitive region and its physiological functions are maintained.

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References

  • Bernstein KA, Gangloff S, Rothstein R (2010) The RecQ DNA helicases in DNA repair. Ann Rev Genet 44:393–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bhalla N, Biggins S, Murray AW (2002) Mutation of YCS4, a budding yeast condensin subunit, affects mitotic and nonmitotic chromosome behavior. Mol Biol Cell 13:632–645

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Blackburn EH, Gall JG (1978) A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in tetrahymena. J Mol Biol 120:33–53

    Article  CAS  PubMed  Google Scholar 

  • Burkhalter MD, Sogo JM (2004) rDNA enhancer affects replication initiation and mitotic recombination. Mol Cell 15:409–421

    Article  CAS  PubMed  Google Scholar 

  • Christman MF, Dietrich FS, Fink GR (1988) Mitotic recombination in the rDNA of S. Cerevisiae is suppressed by the combined action of DNA topoisomerases I and II. Cell 55:413–425

    Article  CAS  PubMed  Google Scholar 

  • Defossez PA, Prusty R, Kaeberlein M, Lin SJ, Ferrigno P, Silver PA, Keil RL, Guarente L (1999) Elimination of replication fork block protein Fob1 extends the life span of yeast mother cells. Mol Cell 3:447–455

    Article  CAS  PubMed  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221

    Article  CAS  PubMed  Google Scholar 

  • Driscoll R, Hudson A, Jackson SP (2007) Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56. Science 315:649–652

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J (1995) The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 83:655–666

    Article  CAS  PubMed  Google Scholar 

  • Fangman WL, Brewer BJ (1991) Activation of replication origins within yeast chromosomes. Annu Rev Cell Biol 7:375–402

    Article  CAS  PubMed  Google Scholar 

  • Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall S (1993) The gene responsible for Werner syndrome may be a cell division “counting” gene. Proc Natl Acad Sci U S A 90:12030–12034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Freeman L, Aragon-Alcaide L, Strunnikov A (2000) The condensin complex governs chromosome condensation and mitotic transmission of rDNA. J Cell Biol 149:811–824

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 23:1558–1568

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • French SL, Sikes ML, Hontz RD, Osheim YN, Lambert TE, El Hage A, Smith MM, Tollervey D, Smith JS, Beyer AL (2011) Distinguishing the roles of topoisomerases I and II in relief of transcription-induced torsional stress in yeast rRNA genes. Mol Cell Biol 31:482–494

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gonzalez IL, Sylvester JE (1995) Complete sequence of 43-kb human ribosomal DNA repeat: analysis of the intergenic spacer. Genomics 27:320–328

    Article  CAS  PubMed  Google Scholar 

  • Han J, Zhou H, Horazdovsky B, Zhang K, Xu RM, Zhang Z (2007) Rtt109 acetylates histone H3 lysine 56 and functions in DNA replication. Science 315:653–655

    Article  CAS  PubMed  Google Scholar 

  • Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460

    Article  CAS  PubMed  Google Scholar 

  • Hartwell LH et al (2011) Transposable genetic element. In: Genetics, 4th edn. McGraw Hill, New York pp 447–453

    Google Scholar 

  • Hirano T (2000) Chromosome cohesion, condensation, and separation. Annu Rev Biochem 69:115–144

    Article  CAS  PubMed  Google Scholar 

  • Ide S, Miyazaki T, Maki H, Kobayashi T (2010) Abundance of ribosomal RNA gene copies maintains genome integrity. Science 327:693–696

    Article  CAS  PubMed  Google Scholar 

  • Ide S, Saka K, Kobayashi T (2013) Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast. PLoS Genet 9, e1003410

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jabs EW, Persico MG (1987) Characterization of human centromeric regions of specific chromosomes by means of alphoid DNA sequences. Am J Hum Genet 41:374–390

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in saccharomyces cerevisiae by two different mechanisms. Genes Dev 13:2570–2580

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kobayashi T (2006) Strategies to maintain the stability of the ribosomal RNA gene repeats. Genes Genet Syst 81:155–161

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T (2008) A new role of the rDNA and nucleolus in the nucleus- rDNA instability maintains genome integrity. BioEssays 30:267–272

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T (2011a) Regulation of ribosomal RNA gene copy number and its role in modulating genome integrity and evolutionary adaptability in yeast. Cell Mol Life Sci 64:1395–1403

    Article  Google Scholar 

  • Kobayashi T (2011b) How does genome instability affect lifespan?: roles of rDNA and telomeres. Genes Cells 16:617–624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kobayashi T, Ganley AR (2005) Recombination regulation by transcription-induced cohesin dissociation in rDNA repeats. Science 309:1581–1584

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Heck DJ, Nomura M, Horiuch 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 12:3821–3830

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 117:441–453

    Article  CAS  PubMed  Google Scholar 

  • Krawczyk C, Dion V, Schär P, Fritsch O (2014) Reversible top1 cleavage complexes are stabilized strand-specifically at the ribosomal replication fork barrier and contribute to ribosomal DNA stability. Nucleic Acids Res 42:4985–4995

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Long EO, Dawid IB (1980) Repeated genes in eukaryotes. Annu Rev Biochem 49:727–764

    Article  CAS  PubMed  Google Scholar 

  • McMurray CT (2010) Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 11:786–799

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McMurray M, Gottschling DE (2003) An age-induced switch to a hyper-recombinational state. Science 301:1908–1911

    Article  CAS  PubMed  Google Scholar 

  • Park PU, Defossez PA, Guarente L (1999) Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae. Mol Cell Biol 19:3848–3856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Peng JC, Karpen GH (2008) Epigenetic regulation of heterochromatic DNA stability. Curr Opin Genet Dev 18:204–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ritossa FM (1968) Unstable redundancy of genes for ribosomal RNA. Proc Natl Acad Sci U S A 60:509–516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saka K, Kobayashi T in preparation

    Google Scholar 

  • Saka K, Ide S, Ganley AR, Kobayashi T (2013) Cellular senescence in yeast is regulated by rDNA noncoding transcription. Curr Biol 23:1794–1798

    Article  CAS  PubMed  Google Scholar 

  • Sakai M, Ohta T, Minoshima S, Kudoh J, Wang Y, de Jong PJ et al (1995) Human ribosomal RNA gene cluster: identification of the proximal end containing a novel tandem repeat sequence. Genomics 26:521–526

    Article  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 

  • Santarius T, Shipley J, Brewer D, Stratton MR, Cooper CS (2010) A census of amplified and overexpressed human cancer genes. Nat Rev Cancer 10:59–64

    Article  CAS  PubMed  Google Scholar 

  • Sawan C, Herceg Z (2010) Histone modifications and cancer. Adv Genet 70:57–85

    Article  CAS  PubMed  Google Scholar 

  • Sullivan M, Higuchi T, Katis VL (2004) Uhlmann F Cdc14 phosphatase induces rDNA condensation and resolves cohesin-independent cohesion during budding yeast anaphase. Cell 117:471–482

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi Y, Horiuchi T, Kobayashi T (2003) Transcription-dependent recombination and the role of fork collision in yeast rDNA. Genes Dev 17:1497–1506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsubota T, Berndsen CE, Erkmann JA, Smith CL, Yang L, Freitas MA, Denu JM, Kaufman PD (2007) Histone H3-K56 acetylation is catalyzed by histone chaperone-dependent complexes. Mol Cell 25:703–712

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vogelauer M, Camilloni GS (1999) Site-specific in vivo cleavages by DNA topoisomerase I in the regulatory regions of the 35 S rRNA in Saccharomyces cerevisiae are transcription independent. J Mol Biol 275:197–209

    Article  Google Scholar 

  • Warner JR (1999) The economics of ribosome biosynthesis in yeast. Trends Biochem Sci 24:437–440

    Article  CAS  PubMed  Google Scholar 

  • Yu CE et al (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262

    Article  CAS  PubMed  Google Scholar 

  • Zakian VA (1989) Structure and function of telomeres. Ann Rev Genet 23:579–604

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Takehiko Kobayashi .

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Kobayashi, T. (2016). Genome Instability of Repetitive Sequence: Lesson from the Ribosomal RNA Gene Repeat. In: Hanaoka, F., Sugasawa, K. (eds) DNA Replication, Recombination, and Repair. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55873-6_10

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