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Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation.

Yang JH, Chiou YY, Fu SL, Shih IY, Weng TH, Lin WJ, Lin CH - Nucleic Acids Res. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan.

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Crosstalk between Arg296/Arg299 methylation and Ser302 phosphorylation results in role switch of hnRNPK in DNA damage response. Frequently occurred methylation of Arg296/Arg299 suppresses the PKCδ-mediated Ser302 phosphorylation, which results in the anti-apoptotic effect of hnRNPK. Alternatively, low level of Arg296/Arg299 methylation promotes the nearby Ser302 phosphorylation and pro-apoptotic effect of hnRNPK after DNA damage.
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Figure 10: Crosstalk between Arg296/Arg299 methylation and Ser302 phosphorylation results in role switch of hnRNPK in DNA damage response. Frequently occurred methylation of Arg296/Arg299 suppresses the PKCδ-mediated Ser302 phosphorylation, which results in the anti-apoptotic effect of hnRNPK. Alternatively, low level of Arg296/Arg299 methylation promotes the nearby Ser302 phosphorylation and pro-apoptotic effect of hnRNPK after DNA damage.

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.


Arginine methylation of hnRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation.

Yang JH, Chiou YY, Fu SL, Shih IY, Weng TH, Lin WJ, Lin CH - Nucleic Acids Res. (2014)

Crosstalk between Arg296/Arg299 methylation and Ser302 phosphorylation results in role switch of hnRNPK in DNA damage response. Frequently occurred methylation of Arg296/Arg299 suppresses the PKCδ-mediated Ser302 phosphorylation, which results in the anti-apoptotic effect of hnRNPK. Alternatively, low level of Arg296/Arg299 methylation promotes the nearby Ser302 phosphorylation and pro-apoptotic effect of hnRNPK after DNA damage.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150800&req=5

Figure 10: Crosstalk between Arg296/Arg299 methylation and Ser302 phosphorylation results in role switch of hnRNPK in DNA damage response. Frequently occurred methylation of Arg296/Arg299 suppresses the PKCδ-mediated Ser302 phosphorylation, which results in the anti-apoptotic effect of hnRNPK. Alternatively, low level of Arg296/Arg299 methylation promotes the nearby Ser302 phosphorylation and pro-apoptotic effect of hnRNPK after DNA damage.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming University, Taipei 11221, Taiwan.

Show MeSH
Related in: MedlinePlus