Theranostic Target NSUN2, a C(5)-Methyltransferase, Phospho-Regulatory Network Uncovered with Systematic Assembly of 805 Datasets

The RNA cytosine C(5)-methyltransferase NSUN2 is involved in RNA modification and regulates gene expression and genomic stability. Beyond multiple sequence/copy number variations, NSUN2 displays altered phosphoprotein expression in various cancers and developmental disorders, thereby making it a prime molecular target of relevance to both therapeutics and diagnostics, that is, theranostics. Despite its key role in kinase-regulated pathways and broader biological processes, the phospho-regulatory network of NSUN2 remains largely unexplored. We report here a systematic assembly of 805 phosphoproteomics datasets from the literature, among which 239 datasets showed differential regulation of NSUN2 phosphopeptides and 40 ensembled phosphosites in NSUN2. Significantly, the phosphorylation sites Ser456, Ser743, and Ser751 represented NSUN2 in ∼50% of these datasets. This is notable given that the functional roles of these phosphosites have been previously underappreciated and underrepresented in the scientific literature. Therefore, we implemented a codetection/coregulation approach based on the phosphosites in other proteins that are codifferentially regulated with phosphopeptides of NSUN2. This approach led to our identification of 55 interactors, 4 potential kinases, and 7 other methylases whose phosphopeptides were codifferentially regulated with NSUN2 phosphopeptides. To the best of our knowledge, this study provides the first phosphosite-centric regulatory network model of NSUN2 to employ theranostic strategies for targeting NSUN2 in cancers and other disorders.