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MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis
Author(s) -
Yang ShanZhong,
Lin FangTsyr,
Lin WeeiChin
Publication year - 2008
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.128
Subject(s) - chek1 , e2f1 , dna repair , g2 m dna damage checkpoint , rad51 , dna damage , biology , checkpoint kinase 2 , microbiology and biotechnology , cancer research , genome instability , cell cycle checkpoint , gene , dna , genetics , cell cycle
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.