Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Protection of repetitive DNA borders from self-induced meiotic instability


DNA double strand breaks (DSBs) in repetitive sequences are a potent source of genomic instability, owing to the possibility of non-allelic homologous recombination (NAHR). Repetitive sequences are especially at risk during meiosis, when numerous programmed DSBs are introduced into the genome to initiate meiotic recombination1. In the repetitive ribosomal DNA (rDNA) array of the budding yeast Saccharomyces cerevisiae, meiotic DSB formation is prevented in part through Sir2-dependent heterochromatin formation2,3. Here we show that the edges of the rDNA array are exceptionally susceptible to meiotic DSBs, revealing an inherent heterogeneity in the rDNA array. We find that this localized DSB susceptibility necessitates a border-specific protection system consisting of the meiotic ATPase Pch2 and the origin recognition complex subunit Orc1. Upon disruption of these factors, DSB formation and recombination increased specifically in the outermost rDNA repeats, leading to NAHR and rDNA instability. Notably, the Sir2-dependent heterochromatin of the rDNA itself was responsible for the induction of DSBs at the rDNA borders in pch2Δ cells. Thus, although the activity of Sir2 globally prevents meiotic DSBs in the rDNA, it creates a highly permissive environment for DSB formation at the junctions between heterochromatin and euchromatin. Heterochromatinized repetitive DNA arrays are abundant in most eukaryotic genomes. Our data define the borders of such chromatin domains as distinct high-risk regions for meiotic NAHR, the protection of which may be a universal requirement to prevent meiotic genome rearrangements that are associated with genomic diseases and birth defects.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Ribosomal-DNA-associated DSB formation and recombination.
Figure 2: Association of the meiotic DSB machinery near the rDNA.
Figure 3: Orc1 and Pch2 collaborate to suppress DSB formation.
Figure 4: Ribosomal-DNA chromatin promotes DSB formation.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

All data sets in this publication are available in the NCBI Gene Expression Omnibus (, accession number GSE30073.


  1. Sasaki, M., Lange, J. & Keeney, S. Genome destabilization by homologous recombination in the germ line. Nature Rev. Mol. Cell Biol. 11, 182–195 (2010)

    CAS  Article  Google Scholar 

  2. Gottlieb, S. & Esposito, R. E. A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56, 771–776 (1989)

    CAS  Article  Google Scholar 

  3. Mieczkowski, P. A. et al. Loss of a histone deacetylase dramatically alters the genomic distribution of Spo11p-catalyzed DNA breaks in Saccharomyces cerevisiae . Proc. Natl Acad. Sci. USA 104, 3955–3960 (2007)

    ADS  CAS  Article  Google Scholar 

  4. San-Segundo, P. A. & Roeder, G. S. Pch2 links chromatin silencing to meiotic checkpoint control. Cell 97, 313–324 (1999)

    CAS  Article  Google Scholar 

  5. Wu, H. Y. & Burgess, S. M. Two distinct surveillance mechanisms monitor meiotic chromosome metabolism in budding yeast. Curr. Biol. 16, 2473–2479 (2006)

    CAS  Article  Google Scholar 

  6. Blitzblau, H. G. et al. Mapping of meiotic single-stranded DNA reveals double-stranded-break hotspots near centromeres and telomeres. Curr. Biol. 17, 2003–2012 (2007)

    CAS  Article  Google Scholar 

  7. Gerton, J. L. et al. Inaugural article: global mapping of meiotic recombination hotspots and coldspots in the yeast Saccharomyces cerevisiae . Proc. Natl Acad. Sci. USA 97, 11383–11390 (2000)

    ADS  CAS  Article  Google Scholar 

  8. Petes, T. D. Meiotic recombination hot spots and cold spots. Nature Rev. Genet. 2, 360–369 (2001)

    CAS  Article  Google Scholar 

  9. Keeney, S. Mechanism and control of meiotic recombination initiation. Curr. Top. Dev. Biol. 52, 1–53 (2001)

    CAS  Article  Google Scholar 

  10. Coelho, P. S. et al. A novel mitochondrial protein, Tar1p, is encoded on the antisense strand of the nuclear 25S rDNA. Genes Dev. 16, 2755–2760 (2002)

    CAS  Article  Google Scholar 

  11. Arora, C., Kee, K., Maleki, S. & Keeney, S. Antiviral protein Ski8 is a direct partner of Spo11 in meiotic DNA break formation, independent of its cytoplasmic role in RNA metabolism. Mol. Cell 13, 549–559 (2004)

    CAS  Article  Google Scholar 

  12. Keeney, S. & Neale, M. J. Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation. Biochem. Soc. Trans. 34, 523–525 (2006)

    CAS  Article  Google Scholar 

  13. Borner, G. V., Barot, A. & Kleckner, N. Yeast Pch2 promotes domainal axis organization, timely recombination progression, and arrest of defective recombinosomes during meiosis. Proc. Natl Acad. Sci. USA 105, 3327–3332 (2008)

    ADS  CAS  Article  Google Scholar 

  14. Borde, V. et al. Histone H3 lysine 4 trimethylation marks meiotic recombination initiation sites. EMBO J. 28, 99–111 (2009)

    CAS  Article  Google Scholar 

  15. Bell, S. P. The origin recognition complex: from simple origins to complex functions. Genes Dev. 16, 659–672 (2002)

    CAS  Article  Google Scholar 

  16. Gibson, D. G., Bell, S. P. & Aparicio, O. M. Cell cycle execution point analysis of ORC function and characterization of the checkpoint response to ORC inactivation in Saccharomyces cerevisiae . Genes Cells 11, 557–573 (2006)

    CAS  Article  Google Scholar 

  17. Bell, S. P. et al. The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell 83, 563–568 (1995)

    CAS  Article  Google Scholar 

  18. Hanson, P. I. & Whiteheart, S. W. AAA+ proteins: have engine, will work. Nature Rev. Mol. Cell Biol. 6, 519–529 (2005)

    CAS  Article  Google Scholar 

  19. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

    ADS  CAS  Article  Google Scholar 

  20. Vader, G. & Lens, S. M. Chromosome segregation: taking the passenger seat. Curr. Biol. 20, R879–R881 (2010)

    CAS  Article  Google Scholar 

  21. Moazed, D. Common themes in mechanisms of gene silencing. Mol. Cell 8, 489–498 (2001)

    CAS  Article  Google Scholar 

  22. Hoang, M. L. et al. Competitive repair by naturally dispersed repetitive DNA during non-allelic homologous recombination. PLoS Genet. 6, e1001228 (2010)

    Article  Google Scholar 

  23. Aparicio, O. M., Weinstein, D. M. & Bell, S. P. Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase. Cell 91, 59–69 (1997)

    CAS  Article  Google Scholar 

  24. Bell, S. P. et al. The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell 83, 563–568 (1995)

    CAS  Article  Google Scholar 

  25. Kobayashi, T. Strategies to maintain the stability of the ribosomal RNA gene repeats—collaboration of recombination, cohesion, and condensation. Genes Genet. Syst. 81, 155–161 (2006)

    CAS  Article  Google Scholar 

  26. Chernoff, Y. O., Vincent, A. & Liebman, S. W. Mutations in eukaryotic 18S ribosomal RNA affect translational fidelity and resistance to aminoglycoside antibiotics. EMBO J. 13, 906–913 (1994)

    CAS  Article  Google Scholar 

  27. Peoples, T. L. et al. Close, stable homolog juxtaposition during meiosis in budding yeast is dependent on meiotic recombination, occurs independently of synapsis, and is distinct from DSB-independent pairing contacts. Genes Dev. 16, 1682–1695 (2002)

    CAS  Article  Google Scholar 

  28. James, P., Halladay, J. & Craig, E. A. Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast. Genetics 144, 1425–1436 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Blitzblau, H. G. et al. Mapping of meiotic single-stranded DNA reveals double-stranded-break hotspots near centromeres and telomeres. Curr. Biol. 17, 2003 (2007)

    CAS  Article  Google Scholar 

  30. Blitzblau, H. G. & Hochwagen, A. Genome-wide detection of meiotic DNA double-strand break hotspots using single-stranded DNA. Methods Mol. Biol. 745, 47–63 (2011)

    CAS  Article  Google Scholar 

  31. Loidl, J., Nairz, K. & Klein, F. Meiotic chromosome synapsis in a haploid yeast. Chromosoma 100, 221–228 (1991)

    CAS  Article  Google Scholar 

  32. Hunter, N. & Kleckner, N. The single-end invasion: an asymmetric intermediate at the double-strand break to double-holliday junction transition of meiotic recombination. Cell 106, 59–70 (2001)

    CAS  Article  Google Scholar 

Download references


We thank S. P. Bell, A. Shinohara, N. Hunter, N. Hollingsworth and F. Klein for sharing reagents and data. We thank I. Cheeseman, M. Gehring and V. Subramanian for discussions and critical reading of the manuscript. This work was supported by NIH grant GM088248 to A.H. and by fellowships from the Netherlands Organisation for Scientific Research (NWO Rubicon-825.08.009 and NWO VENI-016.111.004) to G.V.; L.C. was supported by an HHMI Institutional Undergraduate Education Grant to MIT (grant 52005879).

Author information

Authors and Affiliations



G.V., H.G.B. and A.H. designed and performed experiments and analysed the data. M.A.T. performed the yeast two-hybrid analysis. J.E.F., L.C. and A.H. performed recombination mapping. G.V., H.G.B. and A.H. wrote the paper.

Corresponding author

Correspondence to Andreas Hochwagen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-5 with legends, Supplementary Tables 1-3 and additional references. (PDF 1676 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vader, G., Blitzblau, H., Tame, M. et al. Protection of repetitive DNA borders from self-induced meiotic instability. Nature 477, 115–119 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing