Phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks) family include PIP4K2A, PIP4K2B and PIP4K2C isoforms that phosphorylate phosphatidylinositol-5-phosphate on fourth position of inositol ring and catalyse PtdIns(4,5)P2 formation. These enzymes are central to cellular processes such as growth and development, metabolism, and tumour growth. A major limitation towards understanding of how these kinases promote systemic cellular responses and safeguard genomic integrity, is posed by the absence of comprehensive characterization of their downstream target proteins. In order to identify the potential effectors playing downstream of these kinases, we depleted PIP4K2A, PIP4K2B or both in human osteosarcoma cells (U2OS) followed by largescale proteomics analysis. Using LC-MS/MS approach, we report that the downregulation PIP4K2A, PIP4K2B or both, is correlated with mis-regulation of proteins that are involved in cellular processes impairing genome instability. The analysis further revealed impact on a cluster of proteins (including post translational modifications) involved in genome integrity maintenance.