VRK1 regulates SRRM2 phosphorylation to promote the splicing of transcripts encoding DNA damage repair factors

Abstract

Vaccinia-related kinase 1 (VRK1) is a nuclear serine/threonine kinase that contributes to genome stability through the phosphorylation of diverse substrates. VRK1 is frequently upregulated in multiple malignancies. Although its function as a chromatin kinase has been extensively characterized, its potential role in RNA processing remains largely unexplored. Using label-free quantitative phosphoproteomics, we identified the splicing scaffold protein serine/arginine repetitive matrix protein 2 (SRRM2) as a high-confidence VRK1-dependent phosphorylation target. We show that VRK1-dependent SRRM2 phosphorylation is required for efficient alternative splicing of DNA damage response (DDR)-related transcripts and contributes to cellular resistance to genotoxic stress. Collectively, this study reveals that VRK1 supports DDR-related splicing by regulating SRRM2 phosphorylation, providing a novel molecular mechanism by which VRK1 contributes to the DNA damage response.