The roles of cohesins in mitosis, meiosis, and human health and disease

Abstract

Mitosis and meiosis are essential processes that occur during development. Throughout these processes, cohesion is required to keep the sister chromatids together until their separation at anaphase. Cohesion is created by multiprotein subunit complexes called cohesins. Although the subunits differ slightly in mitosis and meiosis, the canonical cohesin complex is composed of four subunits that are quite diverse. The cohesin complexes are also important for DNA repair, gene expression, development, and genome integrity. Here we provide an overview of the roles of cohesins during these different events as well as their roles in human health and disease, including the cohesinopathies. Although the exact roles and mechanisms of these proteins are still being elucidated, this review serves as a guide for the current knowledge of cohesins.

Figure 1

Cohesin subunits form a ring-like structure. SMC1 and SMC3 form a heterodimer, interacting through their hinge regions. The SMC1 and SMC3 head domains, which contain ATPase motifs, interact with the C- and N-termini of the REC8 or RAD21 or RAD21L kleisin subunit, effectively closing the ring. The STAG1 or STAG2 or STAG3 (also called SA1/SA2/SA3) subunit interacts with RAD21 or RAD21L or REC8, contributing to maintenance of the ring structure. Mammalian subunits are shown. Meiosis-specific subunits are depicted as underlined.

Figure 2

Cohesion in yeast mitosis. Cohesin complexes require the Scc2/Scc4 protein complex in order to be loaded on chromosomes. Several proteins act together to establish cohesion during DNA replication. These proteins include Eco1 acetyltransferase, the CTF18-RLC complex, and the polymerase-associated protein Ctf4. Tension at centromeres is generated by the bipolar attachment of kinetochores to the mitotic spindle. Following biorientation of sister chromatids, separase is activated to cleave the Scc1 subunit resulting in removal of cohesin complexes, loss of cohesion, and separation of sister chromatids.

Figure 3

Models of cohesin rings. (A) One ring model predicts that both sister chromatids are entrapped within a single cohesin ring. (B) Another type of ring model, the “handcuff” model, proposes that each of two cohesin rings entraps one sister chromatid, either by binding a single Scc3 subunit or topological interconnection between rings.

Figure 4

Cohesion in yeast meiosis I. Rec8 replaces Scc1 of the cohesin complex in S phase. During prophase I homologous chromosomes pair and meiotic recombination leads to DNA crossovers between non-sister chromatids. In order for homologous chromosomes to segregate, kinetochores of sister chromatid pairs must each be mono-oriented to opposite poles during metaphase I. Separase cleavage of Rec8 during anaphase I, much like that during mitosis, resolves the cohesion distal to crossovers to allow segregation of homologues. In order to allow for the proper biorientation and segregation of sister chromatids during meiosis II, cohesion proximal to centromeres is preserved.

Figure 5

Putative subunit compositions of some of the cohesin complexes in mammals. Differences in spatiotemporal distribution occur throughout the meiotic divisions.