Cohesin Mutations in Cancer and Development

Cohesin is a ring-shaped protein complex that wraps around DNA and is crucial for sister chromatid cohesion, chromatin organization, gene regulation, replication, and DNA damage repair. In somatic cells, it consists of the core ring subunits SMC1A, SMC3, and RAD21 and one of two paralogs, STAG1 or STAG2. Germline mutations in the cohesin ring and its loading complex components cause developmental disorders such as Cornelia de Lange and Roberts syndromes, collectively referred to as cohesinopathies. Similar loss-of-function mutations in cohesin are somatically acquired during cancer development and are prevalent across multiple cancer types, particularly myeloid malignancies, bladder cancer, glioblastoma, and Ewing sarcoma. Here, we discuss the context-dependent effects of cohesin mutations in development and cancer and describe their underlying molecular mechanisms. A deeper understanding of cohesin function in normal development and human disease holds promise to identify new therapeutic opportunities for patients with cohesin dysfunction.