title: Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation.
abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA/DNA-binding protein involved in chromatin remodeling, RNA processing and the DNA damage response. In addition, increased hnRNPK expression has been associated with tumor development and progression. A variety of post-translational modifications of hnRNPK have been identified and shown to regulate hnRNPK function, including phosphorylation, ubiquitination, sumoylation and methylation. However, the functional significance of hnRNPK arginine methylation remains unclear. In the present study, we demonstrated that the methylation of two essential arginines, Arg296 and Arg299, on hnRNPK inhibited a nearby Ser302 phosphorylation that was mediated through the pro-apoptotic kinase PKCδ. Notably, the engineered U2OS cells carrying an Arg296/Arg299 methylation-defective hnRNPK mutant exhibited increased apoptosis upon DNA damage. While such elevated apoptosis can be diminished through addition with wild-type hnRNPK, we further demonstrated that this increased apoptosis occurred through both intrinsic and extrinsic pathways and was p53 independent, at least in part. Here, we provide the first evidence that the arginine methylation of hnRNPK negatively regulates cell apoptosis through PKCδ-mediated signaling during DNA damage, which is essential for the anti-apoptotic role of hnRNPK in apoptosis and the evasion of apoptosis in cancer cells.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan.
authors.forename: Jen-Hao
authors.initials: JH
authors.lastname: Yang
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang Ming University, Taipei 11221, Taiwan.
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Chiou
authors.affiliation: Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Fu
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang Ming University, Taipei 11221, Taiwan.
authors.forename: I-Yun
authors.initials: IY
authors.lastname: Shih
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan.
authors.forename: Tsai-Hsuan
authors.initials: TH
authors.lastname: Weng
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang Ming University, Taipei 11221, Taiwan.
authors.forename: Wey-Jinq
authors.initials: WJ
authors.lastname: Lin
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan Institute of Biopharmaceutical Sciences, National Yang Ming University, Taipei 11221, Taiwan Proteomics Research Center, National Yang Ming University, Taipei 11221, Taiwan chlin2@ym.edu.tw.
authors.forename: Chao-Hsiung
authors.initials: CH
authors.lastname: Lin
mesh_terms: D017209:Apoptosis; D001120:Arginine / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D008745:Methylation / Q000187:drug effects; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000737:chemistry / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D012097:Repressor Proteins; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human; D005047:Etoposide; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D051745:Protein Kinase C-delta; D053148:Caspase 3
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