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RESEARCH PAPER
1 Division of Hematology and Oncology, Department of Medicine, and 2 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA
TopBP1 (DNA topoisomerase II
binding protein I) contains multiple BRCT domains and is involved in replication and the DNA damage checkpoint. Through its BRCT domain, TopBP1 interacts with and represses exclusively E2F1 but not other E2F factors. This regulation of E2F1 transcriptional activity is mediated by a pRb-independent, but Brg1/Brm-dependent mechanism. TopBP1 recruits Brg1/Brm, a central component of the SWI/SNF chromatin-remodeling complex, to E2F1-responsive promoters and represses the activities of E2F1, but not E2F2 or E2F3. This regulation is crucial in the control of E2F1-dependent apoptosis during normal cell growth and DNA damage. Interestingly, TopBP1 is induced by E2F and interacts with E2F1 during G1/S transition. Thus, TopBP1 functions as a critical modulator and serves as a negative feedback regulator of E2F1 by inhibiting E2F1-dependent apoptosis during G1/S transition as well as DNA damage to promote cell survival.
[Keywords: E2F1; TopBP1; apoptosis; Brg1; Brm; BRCT]
Received December 19, 2003; revised version accepted February 25, 2004.
3 Corresponding author.
E-MAIL wclin{at}uab.edu; FAX (205) 975-6911.
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