Etiology and pathogenesis of the cohesinopathies

Musinu Zakari, Kobe Yuen, Jennifer L. Gerton
2015 Wiley Interdisciplinary Reviews: Developmental Biology  
Cohesin is a chromosome-associated protein complex that plays many important roles in chromosome function. Genetic screens in yeast originally identified cohesin as a key regulator of chromosome segregation. Subsequently, work by various groups has identified cohesin as critical for additional processes such as DNA damage repair, insulator function, gene regulation, and chromosome condensation. Mutations in the genes encoding cohesin and its accessory factors result in a group of developmental
more » ... nd intellectual impairment diseases termed 'cohesinopathies.' How mutations in cohesin genes cause disease is not well understood as precocious chromosome segregation is not a common feature in cells derived from patients with these syndromes. In this review, the latest findings concerning cohesin's function in the organization of chromosome structure and gene regulation are discussed. We propose that the cohesinopathies are caused by changes in gene expression that can negatively impact translation. The similarities and differences between cohesinopathies and ribosomopathies, diseases caused by defects in ribosome biogenesis, are discussed. The contribution of cohesin and its accessory proteins to gene expression programs that support translation suggests that cohesin provides a means of coupling chromosome structure with the translational output of cells. Conflict of interest: The authors have declared no conflicts of interest for this article. consisting of a coiled-coil domain flanked by a hinge domain (created by the foldback) that mediates SMC dimer formation and a head domain with ATPase activity. This family also includes members of the condensin complex (SMC2 and SMC4) and SMC5/6 complex. These complexes are conserved from yeast to human and contribute to the organization of chromosomes. Cohesin is loaded onto chromosomes in G1 in budding yeast and during telophase of the preceding cell division in vertebrates by a complex comprised of NIPBL (also known as Scc2, Saccharomyces cerevisiae, Nipped-B, Drosophila melanogaster) and MAU-2 (also known as Scc4, S. cerevisiae) (Figure 2 ). Cohesin may encircle both sister chromatids or may associate with chromosomes in other ways. The 'handcuff' model proposes that a single cohesin ring encircles one sister chromatid while interacting with a second ring encircling the other sister via the Rad21
doi:10.1002/wdev.190 pmid:25847322 fatcat:o36oxuf24nhxbcabwzcwmgxece