Cohesin Mutations in Cancer: Emerging Therapeutic Targets

Abstract

The cohesin complex is crucial for mediating sister chromatid cohesion and for hierarchal three-dimensional organization of the genome. Mutations in cohesin genes are present in a range of cancers. Extensive research over the last few years has shown that cohesin mutations are key events that contribute to neoplastic transformation. Cohesin is involved in a range of cellular processes; therefore, the impact of cohesin mutations in cancer is complex and can be cell context dependent. Candidate targets with therapeutic potential in cohesin mutant cells are emerging from functional studies. Here, we review emerging targets and pharmacological agents that have therapeutic potential in cohesin mutant cells.

Keywords: cancer; cohesin; synthetic lethal; therapeutics; transcription.

Figure 1

(A) Schematic of the cohesin complex. Cohesin loading and unloading onto chromosomes during cell cycle is dynamic and involves a number of regulators. STAG2 mutations are the most frequent, and inhibition of STAG1 subunit is synthetically lethal with STAG2 mutations. Listed are the cohesin regulators that can be pharmacologically inhibited and their inhibition mainly disrupts cell cycle progression. (B) Cohesin subunit SMC3 acetylation during S phase ensures sister chromatid cohesion.

Figure 2

Cohesin’s role in the hierarchical 3-dimensional organization of the genome. Cohesin association with DNA during interphase is required for formation of DNA loops and organization into TADs. DNA loops allow genes to either connect to their regulatory elements (enhancers) or insulate them from ectopic connections. TADs based on transcription and epigenetic modifications segregate into active and inactive compartments. Cohesin mutation can result in aberrant DNA loops, which leads to transcriptional dysregulation. Pharmacological agents that modulate the epigenetic modifications at gene regulatory elements or directly target gene transcription and associated signaling can be used to interfere with the aberrant gene transcription observed in cohesin mutant cells.

Figure 3

Cohesin’s role in DNA repair. Tightly regulated cohesin dynamics at replication fork ensures its integrity and restart of replication stress-induced stalled fork. Cohesin at DNA breaks facilitates homologous recombination mediated repair. Agents that disrupt DNA repair or DNA replication have been shown to have an increased inhibitory effect on cohesin-insufficient or -depleted cells.