신경세포 DNA손상 보호작용을 지닌 P3 연구

Abstract

P3 is initially identified as a p53 downstream target involved in the ROS generation. Here we report that knockdown of P3 sensitizes cells to UV and radiomimetic drugs, impaired DNA repair, and defects both in intra-S-phase and G2/M checkpoints in response to DNA damage. P3 formed DNA damage-induced nuclear foci that is phosphatidylinositol 3-kinase-like family of serine/threonine protein kinases (PIKKs) dependent. Notably, P3 and g-H2AX coimmunoprecipitate and colocalization in DNA damage foci, and efficient induction and maintenance of H2AX phosphorylation after DNA damage is impaired in P3 knockdown cells. Following DNA damage, P3 colocalized and associated with several DNA damage sensors and mediators, and contribute to the recruitment of these elements on the sites of DNA break lesions. Importantly, early cellular response to DNA damage is suppressed in p53-deficient cells, and expression of P3 in a p53-deficient cells restores g-H2AX signals as well as the recruitment of 53BP1 and Mre11 at DNA breaks, whereas, in p53 gain of function mutant cells, these response is not affected by P3. Our results suggest that P3 contributes to upstream induction of DNA damage signal, depending on the p53 status of the cells, and is an essential for p53-mediated triggering the appropriate early DNA damage response.