Ablation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressor.
Arginine methylation of histones is a well-known regulator of gene expression. Protein arginine methyltransferase 6 (PRMT6) has been shown to function as a transcriptional repressor by methylating the histone H3 arginine 2 [H3R2(me2a)] repressive mark; however, few targets are known. To define the physiological role of PRMT6 and to identify its targets, we generated PRMT6(-/-) mouse embryo fibroblasts (MEFs). We observed that early passage PRMT6(-/-) MEFs had growth defects and exhibited the hallmarks of cellular senescence. PRMT6(-/-) MEFs displayed high transcriptional levels of p53 and its targets, p21 and PML. Generation of PRMT6(-/-); p53(-/-) MEFs prevented the premature senescence, suggesting that the induction of senescence is p53-dependent. Using chromatin immunoprecipitation assays, we observed an enrichment of PRMT6 and H3R2(me2a) within the upstream region of Trp53. The PRMT6 association and the H3R2(me2a) mark were lost in PRMT6(-/-) MEFs and an increase in the H3K4(me3) activator mark was observed. Our findings define a new regulator of p53 transcriptional regulation and define a role for PRMT6 and arginine methylation in cellular senescence.
Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Department of Oncology, McGill University, Montréal, Québec, Canada, H3T 1E2.
Mathieu
M
Neault
Frédérick A
FA
Mallette
Gillian
G
Vogel
Jonathan
J
Michaud-Levesque
Stéphane
S
Richard
D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; C577312:PRMT6 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D018631:ras Proteins