Article

Cohesin Is Limiting for the Suppression of DNA Damage–Induced Recombination between Homologous Chromosomes

Brandeis University, United States of America
PLoS Genetics (Impact Factor: 8.17). 07/2010; 6(7):e1001006. DOI: 10.1371/journal.pgen.1001006
Source: PubMed

ABSTRACT Double-strand break (DSB) repair through homologous recombination (HR) is an evolutionarily conserved process that is generally error-free. The risk to genome stability posed by nonallelic recombination or loss-of-heterozygosity could be reduced by confining HR to sister chromatids, thereby preventing recombination between homologous chromosomes. Here we show that the sister chromatid cohesion complex (cohesin) is a limiting factor in the control of DSB repair and genome stability and that it suppresses DNA damage-induced interactions between homologues. We developed a gene dosage system in tetraploid yeast to address limitations on various essential components in DSB repair and HR. Unlike RAD50 and RAD51, which play a direct role in HR, a 4-fold reduction in the number of essential MCD1 sister chromatid cohesion subunit genes affected survival of gamma-irradiated G(2)/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G(2)/M cells with a single copy of MCD1 or SMC3 even at radiation doses where survival was high and DSB repair was efficient. The increased recombination also extended to nonlethal doses of UV, which did not induce DSBs. The DNA damage-induced recombinants in G(2)/M cells included crossovers. Thus, the cohesin complex has a dual role in protecting chromosome integrity: it promotes DSB repair and recombination between sister chromatids, and it suppresses damage-induced recombination between homologues. The effects of limited amounts of Mcd1and Smc3 indicate that small changes in cohesin levels may increase the risk of genome instability, which may lead to genetic diseases and cancer.

0 Followers
 · 
88 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sister chromatid cohesion (SCC), which is established during DNA replication, ensures genome stability. Establishment of SCC is inhibited in G2. However, this inhibition is relived and SCC is established as a response to DNA damage, a process known as Damage Induced Cohesion (DIC). In yeast, Chk1, which is a kinase that functions in DNA damage signal transduction, is considered an activator of SCC through DIC. Nonetheless, here we show that, unlike SCC mutations, loss of CHK1 did not increase spontaneous or damage-induced allelic recombination or aneuploidy. We suggest that Chk1 has a redundant role in the control of DIC or that DIC is redundant for maintaining genome stability.
    PLoS ONE 12/2014; 9(12):e113435. DOI:10.1371/journal.pone.0113435 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The RAD21 cohesin plays, besides its well-recognised role in chromatid cohesion, a role in DNA double strand break (dsb) repair. In Arabidopsis there are three RAD21 paralog genes (AtRAD21.1, AtRAD21.2 and AtRAD21.3), yet only AtRAD21.1 has been shown to be required for DNA dsb damage repair. Further investigation of the role of cohesins in DNA dsb repair was carried out and is here reported.ResultsWe show for the first time that not only AtRAD21.1 but also AtRAD21.3 play a role in somatic DNA dsb repair. Comet data shows that the lack of either cohesins induces a similar high basal level of DNA dsb in the nuclei and a slower DNA dsb repair kinetics in both cohesin mutants. The observed AtRAD21.3 transcriptional response to DNA dsb induction reinforces further the role of this cohesin in DNA dsb repair. The importance of AtRAD21.3 in DNA dsb damage repair, after exposure to DNA dsb damage inducing agents, is notorious and recognisably evident at the phenotypical level, particularly when the AtRAD21.1 gene is also disrupted.Data on the kinetics of DNA dsb damage repair and DNA damage sensitivity assays, of single and double atrad21 mutants, as well as the transcription dynamics of the AtRAD21 cohesins over a period of 48 hours after the induction of DNA dsb damage is also shown.Conclusions Our data demonstrates that both Arabidopsis cohesin (AtRAD21.1 and AtRAD21.3) play a role in somatic DNA dsb repair. Furthermore, the phenotypical data from the atrad21.1 atrad21.3 double mutant indicates that these two cohesins function synergistically in DNA dsb repair. The implications of this data are discussed.
    BMC Plant Biology 12/2014; 14(1):353. DOI:10.1186/s12870-014-0353-9 · 3.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Eukaryotic organisms maintain karyotypes with constant chromosome number, but polyploid cells that contain more than two sets of chromosomes can be frequently found. On one hand, polyploidization is likely to provide some beneficial effects, as naturally occurring polyploid cells can be readily found. On the other hand, polyploidization profoundly affects cell physiology, which may be detrimental to cells. Additionally, polyploidy leads often to aneuploidy and diversification of genetic information, therefore it has always been considered a prominent driving force in evolution. Recently tetraploid-derived aneuploidy was suggested as a possible mechanism for resistance to fungicides. Another prominent example of the effects of tetraploid-derived aneuploidy is cancer where up to 1/3 of tumors likely originated through a tetraploid intermediates. Studying the cellular consequences of polyploidization in human cells is challenging. In contrast, polyploid and aneuploid cells can be easily generated and analyzed in the budding yeast Saccharomyces cerevisiae as well as in other yeast species. This together with the naturally occurring yeast polyploids and aneuploids provide a valuable model to study the effects of abnormal chromosome numbers on cellular physiology. Thus, the yeast model may provide novel insights into the general mechanisms of genomic instability in eukaryotes and improve our understanding of the consequences of ploidy changes and their relevance for diseases. This article is protected by copyright. All rights reserved.
    Yeast 11/2014; 31(11). DOI:10.1002/yea.3037 · 1.74 Impact Factor

Full-text (3 Sources)

Download
29 Downloads
Available from
May 21, 2014