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

Yongjun Tan1, Pradip Raychaudhuri, Robert H Costa

  • 1Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA. ytan1231@yahoo.com.

Molecular and Cellular Biology
|November 15, 2006
PubMed

Insights

The transcription factor forkhead box M1 (FoxM1) is crucial for DNA repair. DNA damage triggers checkpoint kinase 2 (Chk2) to stabilize FoxM1, enhancing DNA repair gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The transcription factor forkhead box M1 (FoxM1) plays a key role in cell cycle regulation, DNA replication, and mitosis.
  • Its involvement in DNA repair mechanisms, particularly in response to DNA damage, is not fully understood.

Purpose of the Study:

  • To investigate the role of FoxM1 in DNA damage response and repair.
  • To elucidate the mechanism by which FoxM1 influences DNA repair gene expression.

Main Methods:

  • Utilized FoxM1-deficient mouse embryonic fibroblasts and U2OS cells with reduced FoxM1 levels via siRNA.
  • Assessed DNA breaks using phosphospecific histone H2AX staining.
  • Measured p53 transcriptional activity and expression of DNA repair genes (XRCC1, BRCA2).
  • Investigated FoxM1 phosphorylation by checkpoint kinase 2 (Chk2) in response to DNA damage.

Main Results:

  • FoxM1 deficiency led to increased DNA breaks and elevated p53 transcriptional activity (p21(cip1) expression).
  • Reduced expression of base excision repair factor XRCC1 and homologous recombination repair factor BRCA2 was observed in FoxM1-deficient cells.
  • Checkpoint kinase 2 (Chk2) phosphorylates FoxM1 at serine 361 upon DNA damage.
  • Phosphorylation stabilized FoxM1, leading to increased transcription of XRCC1 and BRCA2.

Conclusions:

  • FoxM1 is essential for the transcriptional response to DNA damage.
  • Chk2-mediated phosphorylation of FoxM1 stabilizes the protein and upregulates key DNA repair genes (XRCC1, BRCA2).
  • This study reveals a novel mechanism for regulating DNA repair enzyme expression through the FoxM1-Chk2 pathway.

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