Regulated recruitment of tumor suppressor BRCA1 to the p21 gene by coactivator methylation.
Tumor suppression by p53 and BRCA1 involves regulation of cell cycle, apoptosis, and DNA repair and is influenced by transcriptional coactivators and post-translational modifications. Here we show that coactivator-associated arginine methyltransferase 1 (CARM1) methylates Arg 754 in the KIX region of coactivator p300. Methylated p300 and p300 protein fragments are preferentially recognized by BRCT domains of BRCA1, identifying the BRCT domain as a novel methylarginine-binding module. CARM1 and p300 cooperate with BRCA1 and p53 to induce expression of the critical cell cycle and proliferation regulator p21(WAF1/CIP1) in response to DNA damage. This induction was severely attenuated by elimination of CARM1 or its methyltransferase activity, or by mutation of Arg 754 of p300. Absence of CARM1 methyltransferase activity led to failure of cells to arrest in the G1 phase of the cell cycle in response to DNA damage. CARM1 methyltransferase activity was required for induction of some p53 target genes (p21 and Gadd45) but not others (Bax) by DNA damage. Recruitment of BRCA1 to the p53-binding region of the p21 promoter in response to DNA damage required methylation of Arg 754 of p300 by CARM1. Thus, coactivator methylation may be crucial for fine-tuning the tumor suppressor function of BRCA1 and other BRCT domain proteins.
Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089, USA.
Young-Ho
YH
Lee
Mark T
MT
Bedford
Michael R
MR
Stallcup
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004249:DNA Damage; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008745:Methylation; D051379:Mice; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
D019313:BRCA1 Protein; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D050880:p300-CBP Transcription Factors
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