Phosphosite-centric regulatory network of ATAD2 and its involvement in transcriptional networks

The phosphorylation dependent regulation of transcription factors, transcriptional co-regulators and chromatin remodelling factors influences transcription. Aberrant transcriptional regulations driven by chromatin-associated oncogenic factors are a feature of various cancers; however, their phosphorylation-dependent regulation remains poorly characterised. ATPase family AAA domain-containing protein 2 (ATAD2) is a chromatin-associated factor implicated in oncogenic transcriptions. Here, we present a comprehensive phosphosite-centric analysis of ATAD2 by integrating data from multiple phosphoproteomic studies, encompassing 859 profiling and 285 differential datasets. From the class 1 differentially regulated phosphosites, four predominant phosphosites-S327, S337, S342, and T1152, emerged as consistently regulated and were frequently detected in diverse tumour datasets. The co-differentially phosphorylated proteins, including their interactors and potential upstream kinases (HASPIN, STK10, CDK12, PRP4K, CDK13, PAK4), were involved in cell cycle, chromatin remodelling, transcription, and DNA repair. Several phosphosites in transcription factors were found to be coregulated along with ATAD2 phosphosites. Phosphorylation at S327 and S342 was broadly upregulated and positively associated with transcriptional activators, suggesting a role in promoting transcription. In contrast, phosphorylation at S337 and T1152 correlated with proteins involved in transcriptional repression, indicating its involvement in inhibitory function. Collectively, these findings indicate the involvement of the ATAD2 phosphoregulatory network in transcriptional regulation and provide insights into the regulatory landscape of ATAD2, laying the groundwork for its potential therapeutic targeting in cancers.