Abstract B23: The deubiquitinating enzyme USP37 stabilizes Chk1 to promote the cellular response to replication stress

Ubiquitin-mediated proteolysis is a key regulatory process in cell cycle progression. Recently, we identified mutual antagonism between the deubiquitinase USP37 as and the tumor suppressor APC Cdh1 to regulate S-phase entry. Here we report that elevated USP37 expression correlates with cellular transformation. Depletion of USP37 leads to diminished cellular proliferation and loss of viability in tumor cells. USP37-depleted cells exhibit altered replication kinetics and increased levels of the DNA damage markers γH2AX and 53BP1 as well as increased sensitivity to agents that induce replication stress. Underlying the increased sensitivity, we find that USP37 interacts with the checkpoint kinase Chk1 and its binding partner Claspin and promotes the response to replication stress by stabilizing the active form of Chk1. In turn, activation of Chk1 promotes the down-regulation of APC Cdh1 activity, which requires checkpoint mediated weakening of the USP37-APC Cdh1 interaction. Our data suggest a model whereby the temporally regulated interplay of USP37, APC Cdh1 , and the replication checkpoint machinery promotes the ability of tumor cells to survive their intrinsic replication stress by enhancing replication checkpoint activity and driving the G1/S transition. These data provide an improved understanding of the replication checkpoint, control of APC Cdh1 , and maintenance of genome stability. Citation Format: Mayank Singh, Debjani Pal, Amy C. Burrows, Abbey Messina, Andrew Dickson, Matthew K. Summers. The deubiquitinating enzyme USP37 stabilizes Chk1 to promote the cellular response to replication stress. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B23.