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Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes.

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 and osteosarcoma U2OS cells depleted in FoxM1 levels by small interfering RNA transfection display increased DNA breaks, as evidenced by immunofluorescence focus staining for phosphospecific 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.

Pubmed ID: 17101782 RIS Download

Mesh terms: Amino Acid Sequence | Animals | BRCA2 Protein | Checkpoint Kinase 2 | DNA Breaks | DNA Repair | DNA-Binding Proteins | Etoposide | Fibroblasts | Forkhead Box Protein M1 | Forkhead Transcription Factors | Gene Expression Regulation | Humans | Infrared Rays | Mice | Molecular Sequence Data | Phosphorylation | Protein-Serine-Threonine Kinases | Serine | Signal Transduction | Thermodynamics | Transcription, Genetic | Tumor Suppressor Protein p53 | Ultraviolet Rays

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Associated grants

  • Agency: NIA NIH HHS, Id: R01 AG021842
  • Agency: NIDDK NIH HHS, Id: R01 DK054687
  • Agency: NIDDK NIH HHS, Id: DK 54687
  • Agency: NCI NIH HHS, Id: R01 CA100035
  • Agency: NCI NIH HHS, Id: CA 100035
  • Agency: NCI NIH HHS, Id: CA 77637
  • Agency: NCI NIH HHS, Id: R01 CA077637
  • Agency: NIA NIH HHS, Id: R01 AG 21842

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