The Deubiquitinase USP37 Regulates Chromosome Cohesion and Mitotic Progression

Summary A bipolar mitotic spindle facilitates the equal segregation of chromosomes to two daughter cells. To achieve bipolar attachment of microtubules to kinetochoresof sister chromatids, chromatidsmust remain paired after replication. This cohesion is mediated by the conserved cohesincomplex comprised of SMC1, SMC3, SCC1, and either SA1 or SA2 in humans. Because defects in spindle assembly or sister chromatidcohesion can lead to aneuploidy in daughter cells, proper regulation of these processes is essential for fidelity in chromosome segregation[1]. In an RNAi screen for regulators of spindle assembly, we identify the deubiquitinase USP37 as a regulator of mitotic progression, centrosomeintegrity, and chromosome alignment. USP37 associates with cohesinand contributes to sister chromatidresolution. Cohesion defects are rescued by expression of an RNAi-resistant USP37, but not the catalytically impaired USP37 C350A mutant. Further, USP37 associates with WAPL, a negative regulator of cohesion necessary for cohesinrelease in prophase[2, 3], in a manner dependent on USP37's second and third ubiquitin-interacting motifs. Depletion of USP37 reduces the stability of chromatin-associated WAPL and increases the fraction of WAPL that is more heavily ubiquitylated in mitosis. Consistently, overexpression of USP37 C350A results in increased modification of WAPL, and addition of purified USP37 WT , but not USP37 C350A , to WAPL immunoprecipitates results in a reduction of ubiquitylated products. Taken together, our results ascribe a novel function for USP37 in mitotic progression and further suggest that USP37 positively regulates the stability of chromatin-associated WAPL to facilitate sister chromatidresolution.