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Regulated recruitment of tumor suppressor BRCA1 to the p21 gene by coactivator methylation

Young-Ho Lee1, Mark T Bedford, Michael R Stallcup

  • 1Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089, USA.

Genes & Development
|January 20, 2011
PubMed

Insights

Coactivator-associated arginine methyltransferase 1 (CARM1) methylates p300, enabling BRCA1 to bind and regulate cell cycle arrest. This methylation is crucial for tumor suppressor functions following DNA damage.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Tumor suppression by p53 and BRCA1 is vital for cell cycle regulation, apoptosis, and DNA repair.
  • Transcriptional coactivators and post-translational modifications influence these processes.
  • The role of specific coactivator modifications in tumor suppressor pathways requires further elucidation.

Purpose of the Study:

  • To investigate the role of coactivator-associated arginine methyltransferase 1 (CARM1) in p53 and BRCA1-mediated tumor suppression.
  • To identify the specific mechanism by which CARM1 influences the interaction between coactivators and BRCA1.
  • To determine the functional consequence of CARM1-mediated coactivator modification on DNA damage response pathways.

Main Methods:

  • Mass spectrometry to identify CARM1 methylation sites on p300.
  • Biochemical assays to assess the binding of BRCA1 BRCT domains to methylated p300.
  • Cellular assays to evaluate the impact of CARM1 and p300 modifications on p21(WAF1/CIP1) induction and cell cycle arrest.
  • Chromatin immunoprecipitation to analyze BRCA1 recruitment to target gene promoters.

Main Results:

  • CARM1 methylates Arg 754 in the KIX region of coactivator p300.
  • BRCA1 BRCT domains preferentially recognize methylated p300, identifying a novel methylarginine-binding module.
  • CARM1 and p300 cooperate with BRCA1 and p53 to induce p21(WAF1/CIP1) expression and G1 cell cycle arrest in response to DNA damage.
  • CARM1 methyltransferase activity and Arg 754 methylation are essential for this induction and for BRCA1 recruitment to the p21 promoter.

Conclusions:

  • Coactivator methylation by CARM1 is a critical step in the DNA damage response pathway.
  • CARM1-mediated methylation of p300 enhances BRCA1 binding and facilitates the induction of key tumor suppressor genes like p21.
  • This mechanism highlights the importance of epigenetic modifications in fine-tuning the tumor suppressor functions of BRCA1 and p53.

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