Abstract
PRMT5 participates in various cellular processes, including transcription regulation, signal transduction, mRNA splicing, and DNA repair; however, its mechanism of regulation is poorly understood. Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. Either phosphorylation or substitution of the Y324 residue suppresses PRMT5 activity by preventing its binding with the methyl donor S-adenosyl-L-methionine. Additionally, we show that PRMT5 activity is associated with non-homologous end joining (NHEJ) repair by methylating and stabilizing p53-binding protein 1 (53BP1), which promotes cellular survival after DNA damage. Src-mediated phosphorylation of PRMT5 and the subsequent inhibition of its activity during the DNA damage process blocks NHEJ repair, leading to apoptotic cell death. Altogether, our findings suggest that PRMT5 regulates DNA repair through Src-mediated Y324 phosphorylation in response to DNA damage.
Highlights
PRMT5 participates in various cellular processes, including transcription regulation, signal transduction, mRNA splicing, and DNA repair; its mechanism of regulation is poorly understood
Using the web-based database Scansite, which predicts protein motifs that are likely to be phosphorylated by specific protein kinases, we found that several kinases, including Src kinase, PDGFR, AKT, and ATM, are predicted as the responsible enzymes for phosphorylation of PRMT5 at Y324, T634, and S446 residues, respectively (Supplementary Fig. 1a)
To confirm whether PRMT5 is a novel substrate of Src kinase, we examined the physical interaction between PRMT5 and Src kinase using co-IP assay
Summary
PRMT5 participates in various cellular processes, including transcription regulation, signal transduction, mRNA splicing, and DNA repair; its mechanism of regulation is poorly understood. We show that PRMT5 activity is associated with nonhomologous end joining (NHEJ) repair by methylating and stabilizing p53-binding protein 1 (53BP1), which promotes cellular survival after DNA damage. Src-mediated phosphorylation of PRMT5 and the subsequent inhibition of its activity during the DNA damage process blocks NHEJ repair, leading to apoptotic cell death. We show that PRMT5 activity is regulated by Src kinase-mediated phosphorylation at Y324, a critical residue for its enzymatic activity This phosphorylation occurs in response to DNA damage stresses. PRMT5 participates in the NHEJ repair process by regulating 53BP1 protein levels, and it is critical for cellular survival after DNA damage. Our findings demonstrate the importance of PRMT5 activity in the DNA repair process, which is regulated by Src kinase-mediated Y324 phosphorylation
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