Cohesin Mutations in Cancer

Abstract

Cohesin is a large ring-shaped protein complex, conserved from yeast to human, which participates in most DNA transactions that take place in the nucleus. It mediates sister chromatid cohesion, which is essential for chromosome segregation and homologous recombination (HR)-mediated DNA repair. Together with architectural proteins and transcriptional regulators, such as CTCF and Mediator, respectively, it contributes to genome organization at different scales and thereby affects transcription, DNA replication, and locus rearrangement. Although cohesin is essential for cell viability, partial loss of function can affect these processes differently in distinct cell types. Mutations in genes encoding cohesin subunits and regulators of the complex have been identified in several cancers. Understanding the functional significance of these alterations may have relevant implications for patient classification, risk prediction, and choice of treatment. Moreover, identification of vulnerabilities in cancer cells harboring cohesin mutations may provide new therapeutic opportunities and guide the design of personalized treatments.

Figure 1.

Cohesin composition and architecture. When the Smc1 and Smc3 proteins are folded at their flexible hinge domains, the NTP-binding motif and the DA box present at their amino- and carboxy-terminal globular domains come together to form a functional ATPase. Smc1 and Smc3 interact through their hinges, whereas the kleisin subunit Rad21 bridges their head domains and associates with SA. The outer diameter of the resulting ring-shaped complex is estimated at ∼50 nm and could hold two 10-nm chromatin fibers.

Figure 2.

Cohesin and its regulators throughout the cell cycle. Cohesin is loaded on chromatin by Nipbl-Mau2 throughout the cell cycle, starting in early G₁. Pds5 and Wapl associate with chromatin-bound cohesin and promote its unloading. Cohesin complexes may be encircling a single chromatin fiber or two fibers at the base of a chromatin loop that brings distal regions in proximity. During S phase, acetylation of Smc3 by CoATs Esco1/2 and Sororin recruitment, both facilitated by Pds5A/B (not depicted), results in cohesion establishment. A fraction of cohesin remains dynamic even after DNA replication (not depicted). Whether cohesin at the base of chromatin loops is also involved in tethering sister chromatids is not known. In prophase, most cohesin dissociates from chromatin in a process that requires Wapl and phosphorylation of cohesin and Sororin. Sgo1 and its partner PP2A prevent the dissociation of a population of cohesin, enriched at centromeres. This population is removed at the onset of anaphase when Securin (not depicted) is destroyed and the active Separase cleaves Rad21.

Figure 3.

Cohesin functions. Cohesin plays important roles in several cellular processes involving DNA. These roles rely on the ability of cohesin to hold two DNA strands in trans (the sister chromatids) or in cis (e.g., at the base of a chromatin loop). Accurate chromosome segregation in mitosis and meiosis, HR-mediated DNA repair, and restart and/or protection of stalled replication forks require sister chromatid cohesion (left). DNA looping mediated by cohesin in collaboration with CTCF, Mediator, or transcription factors, among others, likely provides a major organizational principle for the genome (right). This organization regulates transcription both globally, through generation of active/silent domains, and locally, facilitating interactions between enhancer and promoters required for gene activation or RNA Pol II pause release. It also facilitates coordinated origin firing at replication factories and recombination at loci such as IgH or TCRα. For simplicity, a single cohesin ring embracing the two DNA fibers is drawn, but alternative configurations are possible (Eng et al. 2015).

Figure 4.

Cohesin mutations in myeloid malignancies and bladder cancer. Mutation matrix of cohesin subunits, associated factors (PDS5A, PDS5B, WAPL, CDC5A), loaders (NIPBL, MAU2), CoAT/CoDAC (ESCO1, ESCO2, HDAC8), mitotic regulators (SGOL1, ESPL1, PTTG1), and CTCF in AML (A), other myeloid malignancies (B), and bladder cancer (C). Nonsense, frameshift, and splice site mutations are grouped as truncating mutations (red), and missense and inframe indels are labeled as missense mutations (blue). (Data from Ding et al. 2012; Jan et al. 2012; Welch et al. 2012; Balbas-Martinez et al. 2013; Cancer Genome Atlas Research Network 2013, ; Guo et al. 2013; Kon et al. 2013; Yoshida et al. 2013; Lohr et al. 2014; Pellagatti et al. 2014; Thota et al. 2014.)

Figure 5.

Mutations in cohesin complex and related genes in cancer. Bar graph showing mutations in the indicated cancer types for cohesin subunits and cohesin-related genes (grouped as in Fig. 4). (Data obtained from the cBioPortal for Cancer Genomics [Cerami et al. 2012; Gao et al. 2013] and from studies mentioned in Fig. 4.)