Journal
JOURNAL OF CELL BIOLOGY
Volume 193, Issue 2, Pages 267-273Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201010026
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Funding
- National Institutes of Health [CA089239, CA092312, CA100109]
- Department of Defense [W81XWH-05-1-0470]
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Human TopBP1 is a major player in the control of the DNA replication checkpoint. In this study, we identified MDC1, a key checkpoint protein involved in the cellular response to DNA double-strand breaks, as a TopBP1-associated protein. The specific TopBP1-MDC1 interaction is mediated by the fifth BRCT domain of TopBP1 and the Ser-Asp-Thr (SDT) repeats of MDC1. In addition, we demonstrated that TopBP1 accumulation at stalled replication forks is promoted by the H2AX/MDC1 signaling cascade. Moreover, MDC1 is important for ATR-dependent Chk1 activation in response to replication stress. Collectively, our data suggest that MDC1 facilitates several important steps in both cellular DNA damage response and the DNA replication checkpoint.
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