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Multiple endocrine neoplasia type 1 interacts with forkhead transcription factor CHES1 in DNA damage response

Valeria Busygina1, Molly C Kottemann, Kenneth L Scott

  • 1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.

Cancer Research
|September 5, 2006
PubMed

Insights

Multiple endocrine neoplasia type 1 (MEN1) protein menin is crucial for DNA damage response. Menin interacts with CHES1 to activate S-phase arrest, maintaining genomic integrity and preventing tumor formation.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Multiple endocrine neoplasia type 1 (MEN1) is a cancer syndrome linked to menin protein dysfunction.
  • Menin's role in transcriptional regulation suggests involvement in cell proliferation and genomic integrity.
  • The precise mechanism of MEN1 inactivation in tumor development remains unclear.

Purpose of the Study:

  • To investigate the role of the MEN1 protein (menin) in DNA damage response pathways.
  • To elucidate the mechanism by which menin influences cell cycle control following DNA damage.
  • To identify interacting partners of menin involved in DNA damage response.

Main Methods:

  • Utilized Drosophila and mouse embryonic fibroblasts (MEFs) to study MEN1 homologue function.
  • Employed genetic screens to identify interacting proteins, including CHES1 (FOXN3).
  • Performed biochemical assays to confirm interactions between human menin and CHES1.

Main Results:

  • MEN1 mutant tissues showed a deficiency in DNA damage-activated S-phase checkpoint.
  • Overexpression of CHES1 rescued cell cycle arrest and viability in irradiated MEN1 mutant flies.
  • Identified a direct biochemical interaction between menin and CHES1, dependent on menin's COOH terminus.

Conclusions:

  • Menin is essential for activating S-phase arrest in response to ionizing radiation.
  • Menin interacts with the CHES1-mSin3a-HDAC complex, indicating its role in a DNA damage response pathway.
  • Findings suggest menin's function in maintaining genomic integrity is critical for preventing MEN1-associated tumorigenesis.

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