Journal
EMBO REPORTS
Volume 9, Issue 9, Pages 907-915Publisher
WILEY
DOI: 10.1038/embor.2008.128
Keywords
MCPH1/BRIT1; E2F1; p73; Chk1; oligomerization
Categories
Funding
- National Institutes of Health [CA 100857]
- Department of Defense Breast Cancer Research Program [W81XWH-04-1-0442]
- NATIONAL CANCER INSTITUTE [R01CA100857] Funding Source: NIH RePORTER
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Microcephalin (MCPH1) has a crucial role in the DNA damage response by promoting the expression of Checkpoint kinase 1 (CHK1) and Breast cancer susceptibility gene 1 (BRCA1); however, the mechanism of this regulation remains unclear. Here, we show that MCPH1 regulates CHK1 and BRCA1 through the interaction with E2F1 on the promoters of both genes. MCPH1 also regulates other E2F target genes involved in DNA repair and apoptosis such as RAD51, DDB2, TOPBP1, p73 and caspases. MCPH1 interacts with E2F1 on the p73 promoter, and regulates p73 induction and E2F1-induced apoptosis as a result of DNA damage. MCPH1 forms oligomers through the second and third BRCT domains. An MCPH1 mutant containing only its oligomerization domain has a dominant-negative role by blocking MCPH1 binding to E2F1. It also inhibits p73 induction in DNA damage and E2F1-dependent apoptosis. Taken together, MCPH1 cooperates with E2F1 to regulate genes involved in DNA repair, checkpoint and apoptosis, and might participate in the maintenance of genomic integrity.
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