Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation.
Bottom Line: In addition, increased hnRNPK expression has been associated with tumor development and progression.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.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.
Affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan.Show MeSH
Related in: MedlinePlus
Mentions: In summary, the present study demonstrated that the functional crosstalk between the arginine methylation and PKCδ-mediated phosphorylation of hnRNPK regulates cell apoptosis upon DNA damage. Notably, hnRNPK has been correlated with cancer progression and resistance to etoposide-induced DNA damage (71). This is the first report to establish a correlation between hnRNPK methylation and cell apoptosis. Notably, the induced apoptosis by methylation-defective hnRNPK occurred through both intrinsic and extrinsic pathways in a partially p53-independent manner. As shown in Figure 10, we hypothesized that the frequently found Arg296 and Arg299 methylation maintains a low Ser302 phosphorylation level in hnRNPK to support its anti-apoptotic role after DNA damage. However, loss of Arg296 and Arg299 methylation in hnRNPK elevates Ser302 phosphorylation level and promotes apoptosis, implicating that methylation-defective hnRNPK might sensitize cancer cells to etoposide-induced apoptosis. Therefore, the aggressive regulation of arginine methylation may serve as a putative anticancer strategy.
Affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan.