Abstract 2119: DDB2 and XPC influence ATR and ATM recruitment and regulate DNA damage response upon UV irradiation

Abstract

Abstract DNA damage response (DDR) pathways control the activation of DNA repair mechanisms, the activation and eventual release of cell cycle checkpoints to prevent replication of damaged DNA, and apoptosis as a last resort. These processes suggest the coordination of numerous proteins required to preserve genomic integrity. ATR and ATM kinases are central to checkpoint activation in response to DNA damage and replication stress. Activated ATR and ATM phosphorylate several proteins involved in DNA repair and cell cycle arrest. The nature of the signal, which activates ATR and ATM in response to UV damage, is not clear. Here, we showed that DDB2 and XPC, two early damage recognition factors, promote ATR and ATM recruitment and phosphorylation. ATR and ATM localize to the damage site and physically interact with XPC and DDB2. ATR and ATM recruitment and their phosphorylation are affected in cells defective in DDB2 and XPC function. In contrast, ATR- and ATM-deficiency do not regulate DDB2 and XPC recruitment to the damage site. Consequently, phosphorylation of ATR and ATM substrates Chk1, Chk2, H2AX, and BRCA1 was significantly reduced or abrogated in mutated cells, indicating that defective DDB2 and XPC function impair checkpoint signal transduction cascade in response to UV damage. Furthermore, DDB2 and XPC also regulate BRCA1 and Rad51 recruitment to the damage site, implicating their role in homologous recombination-mediated DNA repair pathway. Collectively, these data showed that ATR and ATM are present in the preincision complex with XPC, and influence DNA repair and checkpoint signaling pathways. In support of this, we revealed that depletion of ATR and ATM influence NER efficiency. These results are consistent with a model in which DDB2 and XPC cross-talk with ATR and ATM during maintenance of genomic integrity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2119. doi:1538-7445.AM2012-2119