Damage-induced reactivation of cohesin in postreplicative DNA repair

Abstract

Cohesin establishes sister-chromatid cohesion during S phase to ensure proper chromosome segregation in mitosis. It also facilitates postreplicative homologous recombination repair of DNA double-strand breaks by promoting local pairing of damaged and intact sister chromatids. In G2 phase, cohesin that is not bound to chromatin is inactivated, but its reactivation can occur in response to DNA damage. Recent papers by Koshland's and Sjögren's groups describe the critical role of the known cohesin cofactor Eco1 (Ctf7) and ATR checkpoint kinase in damage-induced reactivation of cohesin, revealing an intricate mechanism that regulates sister-chromatid pairing to maintain genome integrity.

Figure 1

Schematic models for the assembly of cohesin and associated factors at double-strand breaks (DSBs), and ATR- and Eco1 (Ctf7)-dependent reactivation of cohesin in G₂ phase. a: In response to DNA DSB damage, cohesin is recruited to the damage site in a S/G₂ phase-specific manner. This is dependent on the Mre11 complex (Mre11–Rad50–Nbs1), the cohesion-loading factor (Scc2–Scc4), and γH2A. In the case of human cells, the Smc5–Smc6 complex is also required for cohesin recruitment to DSBs. For establishment of sister chromatid cohesion, cohesin requires additional factors, including Eco1 (Ctf7), the Smc5–Smc6 complex, and ATR (see b). b: In G₂ phase, DSBs induce ATR activation, which leads to reactivation of cohesin by Eco1 (Ctf7). Mre11 and the Smc5–Smc6 complex may be involved in the same pathway. This process requires the acetyltransferase activity of Eco1 (Ctf7). The targets of ATR-mediated phosphorylation and Eco1 (Ctf7)-mediated acetylation are unknown.