Interactome of vertebrate GAF/ThPOK reveals its diverse functions in gene regulation and DNA repair

Evolutionary conservation and lineage-specific diversification of existing proteins forms the basis for evolving complexity of protein-protein interaction networks and presumably, thereby that of organism. GAGA associated factor (GAF) belongs to BTB/POZ and zinc finger family of transcription factors and it is conserved from flies to humans. Emerging evidence shows indispensable roles of vertebrate GAF (vGAF a.k.a. ThPOK) in functionally divergent developmental processes like hematopoiesis, adipogenesis and lactation. vGAF is a sequence-specific DNA binding transcription factor with multiple context-dependent roles in gene activation/repression, enhancer-blocking and more recently, it has shown to be the part of ribonucleoprotein complexes as well. In order to understand the molecular basis of these diverse functions, we analyzed the protein-protein interactome of vGAF. This analysis shows vGAFs association with chromatin remodelers, RNA metabolic machinery, transcriptional activators/repressors, and components of DNA repair machinery, thereby provides a plausible explanation for the diverse molecular functions of vGAF. Our findings discern novel role of vGAF in several molecular processes like DNA repair and RNA metabolism. We further tested the biological significance of our protein-protein interaction data and show a novel function of vGAF in DNA repair and cell-survival after UV induced DNA damage. Consistent with these results, analysis of high-throughput RNA-seq data shows the downregulation of vGAF in samples of skin cutaneous melanoma for which the primary cause is UV induced DNA damage. These findings suggest vGAF as an early diagnostic biomarker for skin cutaneous melanoma. Taken together, our study reveals a molecular basis for the diverse functions of vGAF. We uncover its role in DNA repair and provide an explanation for key roles of such evolutionary conserved factors in processes like development and disease. O_TBL View this table: org.highwire.dtl.DTLVardef@900b68org.highwire.dtl.DTLVardef@dcdf49org.highwire.dtl.DTLVardef@c754f1org.highwire.dtl.DTLVardef@999a9dorg.highwire.dtl.DTLVardef@75c91c_HPS_FORMAT_FIGEXP M_TBL C_TBL