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Mol. Cell. Biol. doi:10.1128/MCB.01068-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Chk2 Mediates Stabilization of the FoxM1 Transcription Factor to Stimulate Expression of DNA Repair Genes

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60607; Biomedical Engineering Center and State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China

^* To whom correspondence should be addressed. Email: ytan1231{at}yahoo.com,

	Abstract

The Forkhead Box M1 (FoxM1) transcription factor regulates expression of cell cycle genes essential for DNA replication and mitosis during organ repair and cancer progression. Here, we demonstrate that FoxM1 deficient (-/-) mouse embryonic fibroblasts (MEFs) and osteosarcoma U2OS cells depleted in FoxM1 levels by siRNA transfection display increased DNA breaks as evidenced by immunofluorescence foci staining for phospho-specific Histone H2AX. FoxM1 deficient cells also exhibit stimulation of p53 transcriptional activity as evidenced by increased expression of the p21^cip1 gene. FoxM1 deficient cells display reduced expression of the base excision repair factor X-ray cross-complementing group 1 (XRCC1) and breast cancer associated gene 2 (BRCA2), the latter of which is involved in homologous recombination repair of DNA double strand breaks. Furthermore, FoxM1 protein is phosphorylated by checkpoint kinase 2 (Chk2) in response to DNA damage. This phosphorylation of FoxM1 on Serine residue 361 caused increased stability of the FoxM1 protein with corresponding increased transcription of XRCC1 and BRCA2 genes, both of which are required for repair of DNA damage. These results identify a novel role for FoxM1 in the transcriptional response during DNA damage/checkpoint signaling and show a novel mechanism by which Chk2 protein regulates expression of DNA repair enzymes.

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