Protection of repetitive DNA borders from self-induced meiotic instability
Open Access
- 7 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 477 (7362), 115-119
- https://doi.org/10.1038/nature10331
Abstract
Breakages in repetitive ribosomal DNA (rDNA) sequences can lead to rearrangements through non-allelic homologous recombination, a common source of genomic instability and human disease. Programmed breaks are an essential event in meiosis, however. Vader et al. have identified two proteins, Pch2 and Orc1, that protect the repetitive rDNA array from inappropriate breakages. Surprisingly, Sir2, which establishes the protective heterochromatin environment at rDNA, also makes the border between this heterochromatin and the neighbouring euchromatin susceptible to breaks. Such junctions are therefore at high risk for non-allelic homologous recombination in meiosis. 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.Keywords
This publication has 28 references indexed in Scilit:
- Competitive Repair by Naturally Dispersed Repetitive DNA during Non-Allelic Homologous RecombinationPLoS Genetics, 2010
- Genome destabilization by homologous recombination in the germ lineNature Reviews Molecular Cell Biology, 2010
- Histone H3 lysine 4 trimethylation marks meiotic recombination initiation sitesThe EMBO Journal, 2008
- Yeast Pch2 promotes domainal axis organization, timely recombination progression, and arrest of defective recombinosomes during meiosisProceedings of the National Academy of Sciences of the United States of America, 2008
- Loss of a histone deacetylase dramatically alters the genomic distribution of Spo11p-catalyzed DNA breaks in Saccharomyces cerevisiaeProceedings of the National Academy of Sciences of the United States of America, 2007
- Two Distinct Surveillance Mechanisms Monitor Meiotic Chromosome Metabolism in Budding YeastCurrent Biology, 2006
- Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulationBiochemical Society Transactions, 2006
- AAA+ proteins: have engine, will workNature Reviews Molecular Cell Biology, 2005
- 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 contactsGenes & Development, 2002
- The Single-End Invasion: An Asymmetric Intermediate at the Double-Strand Break to Double-Holliday Junction Transition of Meiotic RecombinationCell, 2001