Protection of repetitive DNA borders from self-induced meiotic instability

Gerben Vader, Hannah G. Blitzblau, Mihoko A. Tame, Jill E. Falk, Lisa Curtin, Andreas Hochwagen

Research output: Contribution to journalArticle

Abstract

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 recombination. In the repetitive ribosomal DNA (rDNA) array of the budding yeast Saccharomyces cerevisiae, meiotic DSB formation is prevented in part through Sir2-dependent heterochromatin formation. 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 pch2 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.

Original languageEnglish (US)
Pages (from-to)115-121
Number of pages7
JournalNature
Volume477
Issue number7362
DOIs
StatePublished - Sep 1 2011

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Ribosomal DNA
DNA
Oligonucleotide Array Sequence Analysis
Heterochromatin
Homologous Recombination
Nucleic Acid Repetitive Sequences
Genome
Genetic Recombination
Origin Recognition Complex
Euchromatin
Saccharomycetales
Double-Stranded DNA Breaks
Genomic Instability
Meiosis
Chromatin
Saccharomyces cerevisiae
Adenosine Triphosphatases

ASJC Scopus subject areas

  • General

Cite this

Vader, G., Blitzblau, H. G., Tame, M. A., Falk, J. E., Curtin, L., & Hochwagen, A. (2011). Protection of repetitive DNA borders from self-induced meiotic instability. Nature, 477(7362), 115-121. https://doi.org/10.1038/nature10331

Protection of repetitive DNA borders from self-induced meiotic instability. / Vader, Gerben; Blitzblau, Hannah G.; Tame, Mihoko A.; Falk, Jill E.; Curtin, Lisa; Hochwagen, Andreas.

In: Nature, Vol. 477, No. 7362, 01.09.2011, p. 115-121.

Research output: Contribution to journalArticle

Vader, G, Blitzblau, HG, Tame, MA, Falk, JE, Curtin, L & Hochwagen, A 2011, 'Protection of repetitive DNA borders from self-induced meiotic instability', Nature, vol. 477, no. 7362, pp. 115-121. https://doi.org/10.1038/nature10331
Vader, Gerben ; Blitzblau, Hannah G. ; Tame, Mihoko A. ; Falk, Jill E. ; Curtin, Lisa ; Hochwagen, Andreas. / Protection of repetitive DNA borders from self-induced meiotic instability. In: Nature. 2011 ; Vol. 477, No. 7362. pp. 115-121.
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