title: Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase δ catalytic subunit gene, POLD1.
abstract: Covalent modification of histones by protein arginine methyltransferases (PRMTs) impacts genome organization and gene expression. In this report, we show that PRMT7 interacts with the BRG1-based hSWI/SNF chromatin remodeling complex and specifically methylates histone H2A Arg-3 (H2AR3) and histone H4 Arg-3 (H4R3). To elucidate the biological function of PRMT7, we knocked down its expression in NIH 3T3 cells and analyzed global gene expression. Our findings show that PRMT7 negatively regulates expression of genes involved in DNA repair, including ALKBH5, APEX2, POLD1, and POLD2. Chromatin immunoprecipitation (ChIP) revealed that PRMT7 and dimethylated H2AR3 and H4R3 are enriched at target DNA repair genes in parental cells, whereas PRMT7 knockdown caused a significant decrease in PRMT7 recruitment and H2AR3/H4R3 methylation. Decreased PRMT7 expression also resulted in derepression of target DNA repair genes and enhanced cell resistance to DNA-damaging agents. Furthermore, we show that BRG1 co-localizes with PRMT7 on target promoters and that expression of a catalytically inactive form of BRG1 results in derepression of PRMT7 target DNA repair genes. Remarkably, reducing expression of individual PRMT7 target DNA repair genes showed that only the catalytic subunit of DNA polymerase, POLD1, was able to resensitize PRMT7 knock-down cells to DNA-damaging agents. These results provide evidence for the important role played by PRMT7 in epigenetic regulation of DNA repair genes and cellular response to DNA damage.
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
authors: Vrajesh
authors: V
authors: Karkhanis
authors: Li
authors: L
authors: Wang
authors: Sookil
authors: S
authors: Tae
authors: Yu-Jie
authors: YJ
authors: Hu
authors: Anthony N
authors: AN
authors: Imbalzano
authors: Saïd
authors: S
authors: Sif
mesh_terms: D000071502:AlkB Homolog 5, RNA Demethylase; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics; D004258:DNA Polymerase III / Q000096:biosynthesis* / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis / Q000235:genetics; D049308:Dioxygenases / Q000096:biosynthesis / Q000235:genetics; D004720:Endonucleases / Q000096:biosynthesis / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008745:Methylation; D051379:Mice; D064251:Multifunctional Enzymes; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D006657:Histones; D008565:Membrane Proteins; D064251:Multifunctional Enzymes; D009687:Nuclear Proteins; D014157:Transcription Factors; D049308:Dioxygenases; C559920:ALKBH5 protein, human; D000071502:AlkB Homolog 5, RNA Demethylase; C487994:PRMT7 protein, human; C570798:PRMT7 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; C434055:POLD1 protein, human; D004258:DNA Polymerase III; C476886:Apex2 protein, mouse; D004720:Endonucleases; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; C530688:APEX2 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase