DNA Damage Response Pathway Uses Histone Modification to Assemble a Double-Strand Break-Specific Cohesin Domain

Abstract

The postreplicative repair of double-strand breaks (DSBs) is thought to require sister chromatid cohesion, provided by the cohesin complex along the chromosome arms. A further specialized role for cohesin in DSB repair is suggested by its de novo recruitment to regions of DNA damage in mammals. Here, we show in budding yeast that a single DSB induces the formation of a approximately 100 kb cohesin domain around the lesion. Our analyses suggest that the primary DNA damage checkpoint kinases Mec1p and Tel1p phosphorylate histone H2AX to generate a large domain, which is permissive for cohesin binding. Cohesin binding to the phospho-H2AX domain is enabled by Mre11p, a component of a critical repair complex, and Scc2p, a component of the cohesin loading machinery that is necessary for sister chromatid cohesion. We also provide evidence that the DSB-induced cohesin domain functions in postreplicative repair.

Turning off the G2 DNA damage checkpoint

“…Among these are histone H2A in the yeasts, and the variant H2A, H2A-X in higher organisms [11]. The phosphorylated histones can span for 50-100kb either side of a double-stranded DNA break (DSB) and serves, at least in part, to recruit cohesin complexes to facilitate recombination [12].…”

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

“…The eukaryotic chromosome is packaged into chromatin, which adds additional complexity to the control of all chromosomal processes, including recombination [45][46][47][48]. Unlike E. coli, eukaryotic chromosomes possess numerous potential origins of replication, of which only a fraction are used to initiate DNA synthesis in each cell cycle.…”

“…Phosphorylation of H2AX ("γ-H2AX") is a rapid, evolutionarily conserved event in the DSB response of eukaryotes and marks chromatin for hundreds of kilobases flanking the DSB [129]. H2AX contributes to DSBR, including SCR, by mechanisms that may involve cohesin complexes [46][47][48]130,131]. This "double life" of BRCA1 on ssDNA and on chromatin further underscores the diversity of functions of this protein, which include HR control, transcriptional regulation/gene silencing and DNA damage checkpoint control.…”

Chromatin dynamics coupled to DNA repair

“…RSC may be involved in cohesin loading at the break due to its analogous role in loading cohesin on chromosome arms during the cell cycle. 109 Cohesins facilitate the repair of DSBs by maintaining the two sister chromatids in close proximity for repair by HR 110,111 and they are also recruited to breaks in a γH2AX-and Mre11-dependent way. 110 Mre11 may recruit RSC in order to facilitate the loading of cohesin at the break.…”

“…109 Cohesins facilitate the repair of DSBs by maintaining the two sister chromatids in close proximity for repair by HR 110,111 and they are also recruited to breaks in a γH2AX-and Mre11-dependent way. 110 Mre11 may recruit RSC in order to facilitate the loading of cohesin at the break. 45,108 The SWI/SNF chromatin remodeling complex, initially identified as an important factor in yeast transcription, is also directly involved in DSB repair.…”