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

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 G2/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G2/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 G2/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.

Deregulation of RAD21 and RUNX1 expression in endometrial cancer

“…The examined markers correlated with each other, partially unraveling the network of genes involved in endometrial tumorigenesis. Findings of previous studies have suggested that the decreased expression of cohesins results in an inappropriate increase in homologous recombination which may drive tumorigenesis through the promotion of genomic instability, such as loss of heterozygosity (15,33,34).…”

Understanding the origins of UV-induced recombination through manipulation of sister chromatid cohesion

“…7, 33 Recently, we found that by events without associated crossovers. For example, sequential repair of two UV lesions found on opposite strands but distant from each other may result in a 4:0 ratio.…”

“…Although cohesin is required for recombinational repair of DSBs in G 2 , cells are capable of repair at a semi-permissive temperature. 33 Overnight cultures grown at permissive temperature (23°C) were diluted and grown to logarithmic phase at permissive (green in Fig. 3), or semi-permissive temperature, 30°C (red in Fig.…”

Cohesin and chromatin organisation

“…Cohesin is essential for DNA repair and chromosome segregation [1,2]. Heterozygous cohesin mutations are the cause of multi-systems developmental disorder such as Cornelia de Lange syndrome [3][4][5], and cohesin mutations have also been reported in cancer [6][7][8].…”

“…Aptly named 'SMC' proteins for 'structural maintenance of chromosomes' cohesin, condensin and Smc5/6 complexes maintain the integrity of genetic information by enabling postreplicative DNA repair, shaping chromosomes in preparation for cell division, and holding sister chromatids together to ensure that daughter cells receive a full complement of chromosomes.Cohesin is essential for DNA repair and chromosome segregation [1,2]. Heterozygous cohesin mutations are the cause of multi-systems developmental disorder such as Cornelia de Lange syndrome [3][4][5], and cohesin mutations have also been reported in cancer [6][7][8].…”