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The genomes of all living organisms are exposed to a wide spectrum of insults. To maintain genomic integrity, eukaryotes have evolved an elaborate surveillance mechanism - DNA damage checkpoint signaling - to detect damaged DNA and to arrest cell cycle progression, allowing time to process and repair DNA damage. TopBP1 plays multiple roles in the regulation of DNA damage checkpoint signaling. However, the molecular mechanism of how TopBP1 regulates ATR-mediated Chk1 phosphorylation is poorly understood. In this communication, we demonstrate (1) that the Chk1 activation domain of TopBP1 is critical in response to several different types of DNA damage; (2) that WD40-repeat protein WDR18 associates with the C-terminus of TopBP1 in vitro and in vivo; (3) that the association between WDR18 and TopBP1 is required for AT70-induced Chk1 phosphorylation; (4) and that WDR18 itself is required for AT70-triggered Chk1 phosphorylation. In addition, WDR18 associates with Chk1 in vitro. The data suggest that WDR18 facilitates ATR-dependent Chk1 phosphorylation via interacting with both C-terminus of TopBP1 and Chk1. Our findings indicate that WDR18 is a bona fide checkpoint protein and that WDR18 works together with TopBP1 to promote DNA damage checkpoint signaling.
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