The Emerging Role of Cohesin in the DNA Damage Response

Abstract

Faithful transmission of genetic material is crucial for all organisms since changes in genetic information may result in genomic instability that causes developmental disorders and cancers. Thus, understanding the mechanisms that preserve genome integrity is of fundamental importance. Cohesin is a multiprotein complex whose canonical function is to hold sister chromatids together from S-phase until the onset of anaphase to ensure the equal division of chromosomes. However, recent research points to a crucial function of cohesin in the DNA damage response (DDR). In this review, we summarize recent advances in the understanding of cohesin function in DNA damage signaling and repair. First, we focus on cohesin architecture and molecular mechanisms that govern sister chromatid cohesion. Next, we briefly characterize the main DDR pathways. Finally, we describe mechanisms that determine cohesin accumulation at DNA damage sites and discuss possible roles of cohesin in DDR.

Keywords: DNA damage tolerance; DNA double-strand breaks; cohesin; cohesin loader; replication stress.

Figure 1

The cohesin complex. Cohesin is composed of Smc1 and Smc3 proteins that contain two globular domains, called the hinge and the head, separated by a long coiled-coil domain. Smc1 and Smc3 interact with each other through the hinge and the head domains. The hinge domain is the possible entry gate for the DNA while the head is an ATPase. Scc1 binds Smc3 and Smc1 with its N- and C-terminus, respectively, completing the cohesin ring. Pds5 and Scc3 are stably bound cohesin subunits that interact with cohesin through Scc1. Wpl1 binds to cohesin only temporarily through Scc3, Pds5, Scc1, and Smc3.

Figure 2

Possible cohesin cycle in yeast. In the G1 phase of the cell cycle, the cohesin complex does not form because Scc1 is absent (A). In the late G1/early S-phase Scc1 expression is reinduced allowing formation of the complete cohesin complex. Next, the chromatin-bound Scc2–Scc4 complex directs cohesin to specific chromosomal loci and facilitates cohesin loading reaction by creating an entry gate for the DNA, possibly by separating Smc1 and Smc3 hinge domains (B). During the S-phase, Eco1 acetylates some of the cohesins. This prevents Wpl1-dependent cohesin deposition and enables stable entrapment of sister chromatids (C), until mitosis cohesion is maintained by Pds5 and Scc3 (D). At the anaphase onset, the Esp1 separase cleaves Scc1, allowing Hos1 to deacetylate Smc3, which leads to cohesin removal from chromatin (E). Many cohesins loaded in G1/S or later (F) are not acetylated by Eco1 (G), and interact with the chromatin only transiently because Wpl1 imposes Scc1 dissociation from Smc3, creating an exit gate for DNA (H).

Figure 3

Cohesin functions in DNA damage response. (A) DSB induction leads to cohesin accumulation near the break site promoting efficient repair by homologous recombination (HR) using the sister chromatid as a template. (B) Cohesin enables replication completion by keeping sister chromatids in close proximity to allow template switch (TS). (C) In the presence of DNA double-strand breaks (DSB), cohesin becomes phosphorylated by ATM kinase and inhibits DNA synthesis. (D) Cohesin blocks premature entry to mitosis under DNA damage conditions allowing complete accumulation of 53PB adaptor and full activation of CHK2 kinase. (E) Cohesin prevents joining of distal DSBs.