PPM1A Act As KAP1/SIRT1 Phosphatase To Regulate KAP1 And SIRT1

KAP1 is a member of transcriptional intermediary factors, which acts as a scaffold in many transcription regulation complexes. It is indicated in many papers that KAP1 mainly acts as a corepressor in the repression complexes. It is reported that KAP1 related transcription regulation complexes exert functions essential for spermiogenesis and early embryo development. However, the precise mechanism for the regulation of KAP1 activity is still not fully understood.SIRT1 is a NAD+ dependent histone deacetylase, and it acts as a regulator of cellular metabolism in different physiological contexts such as gene transcription silencing, cell cycle and growth regulation, energy metabolism, insulin secretion, angiogenesis, neurop rotection, virus infection and cell aging. SIRT1 deacetylates approximately a dozen known substrates including p53, E2F1, nuclear factorκB, FOXO. Regulation of SIRT1 is gaining increasing importance in the development of innovative treatment strategies for cancer, neurodegenerative disorders and metabolic disease.Using a functional genomic approach, we have identified a protein serine/threonine phosphatase, PPM1A, as KAP1/SIRT1 phosphatase. Overexpression of PPM1A results in dephosphorylation of KAP1 Ser473, knockdown of PPMIA expression enhances UV-induced KAP1 phosphorylation and KAP1 target gene. PPM1A binds to SIRT1; Overexpression of PPM1A results in dephophosrylation of SIRT1 Thr719, suppression SIRT1 deacetylase activity in H3 Lys18. These data suggest that PPMIA play an important role in the cell signaling through dephosphorylating KAP1 and SIRT1.