A Deubiquitinase Protects against Aneuploidy and Tumor Formation

Chromosome segregation errors during mitosis result in aneuploidy, which is present in many cancers and may contribute to tumorigenesis. The mitotic checkpoint prevents such errors by inhibiting the anaphase-promoting complex (APC), an E3 ubiquitin ligase that targets cyclin B1 and securin for degradation until all chromosomes are properly attached to the mitotic spindle. Zhang and colleagues investigated the role of the deubiquitinase (DUB) ubiquitin-specific protease 44 (USP44), which is thought to regulate this checkpoint by limiting APC activation, in mitosis. Although Usp44-deficient mice were viable, indicating that USP44 is dispensable for normal development, Usp44^−/− mouse embryonic fibroblasts (MEF) exhibited an increase in chromosome missegregation and enhanced whole-chromosome aneuploidy, suggesting that USP44 is required to prevent mitotic errors. This phenotype was associated with more rapid progression through mitosis and faster release from mitotic arrest, consistent with a modest checkpoint defect; however, APC inhibition did not correct the chromosome segregation errors in Usp^44−/− MEFs, suggesting that USP44 modulates chromosome stability independently of the mitotic checkpoint. Usp44 deficiency resulted in abnormal spindle geometries early in mitosis, including incomplete separation and aberrant positioning of centrosomes, which were tightly correlated with formation of incorrectly attached lagging chromosomes. The regulation of chromosome segregation by USP44 required its localization to centrosomes via interaction with the centriole protein centrin 2 as well as its DUB activity. Intriguingly, Usp^44−/− mice developed spontaneous tumors, in particular lung adenomas, at a much higher incidence compared with that of wild-type mice, and USP44 expression was decreased in human lung adenocarcinomas and associated with reduced overall survival, implicating USP44 as a tumor suppressor. These results identify a critical role for USP44 in mitosis and suggest that loss of USP44 promotes genomic instability that enhances tumor growth.

Zhang Y, Foreman O, Wigle DA, Kosari F, Vasmatzis G, Salisbury JL, et al. USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J Clin Invest 2012;122:4362–74.

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