PRDM2 and DNA damage response: phosphoregulatory signaling insights

PRDM2 is a histone methyltransferase that regulates gene expression through histone H3 lysine 9 methylation. It is involved in the DNA damage response by controlling chromatin remodeling and maintaining genomic integrity. However, the functional relevance of its phosphorylation remains poorly understood. To address this gap, we systematically characterized PRDM2 phosphosites and their associated phospho-signaling networks using large-scale cellular phosphoproteomics data curated from PubMed-indexed articles. Frequency-based ranking revealed Ser643 and Ser421 as predominant phosphosites, detected across 334 and 141 qualitative datasets and 70 and 47 differential cellular phosphoproteomics datasets, respectively. To explore PRDM2-associated phospho-signaling, expression co-regulation analysis was performed to identify phosphosites in other proteins exhibiting consistently similar or opposing expression patterns relative to the predominant PRDM2 phosphosites. This analysis identified 1,251 phosphosites in other proteins showing high-confidence expression co-regulation with PRDM2 Ser421 and 715 phosphosites with PRDM2 Ser643. Functional enrichment revealed significant associations with cell cycle regulation, chromatin organization, RNA processing, and DNA damage response (DDR) pathways. Notably, phosphosites in 30 DDR-related proteins positively co-regulated with Ser643 and 28 with Ser421. Additionally, ATR was identified as a potential kinase predicted to phosphorylate the predominant PRDM2 sites, and its phosphosites exhibited consistent expression co-regulation with PRDM2 sites. Collectively, this study establishes a comprehensive phospho-signaling framework for PRDM2, uncovering its strong association with DNA damage response pathways and providing mechanistic insights into its regulatory network. Clinical trial registration: This study is not part of any clinical trial.

The online version contains supplementary material available at 10.1007/s13205-026-04782-3.