DNA Damage Response (DDR) is a vital ameliorative action undertaken by cells against various intrinsic and extrinsic genotoxic agents. p53 is an important transcription factor that plays a critical role in mediating cell cycle arrest or apoptosis upon DNA damage. PELP1 is a proto-oncogene and scaffolding protein that functions as a coregulator for a number of nuclear receptors such ERα and transcription factors such as E2F1. In this study, we discovered that PELP1 plays a vital role in p53-mediated DNA damage response. Using p53 wild-type breast cancer cells and PELP1-specific shRNAs, we show that cells lacking PELP1 are less sensitive to various genotoxic agents including etoposide, cisplatin, camptothecin or α-irradiation. PELP1 interacts with p53 upon DNA damage and ChIP analysis revealed that PELP1 is recruited to p53 target gene promoters. Reporter gene assays demonstrated that PELP1 functions as a coactivator of p53 and is required for optimal activation of p53 target genes under genomic stress. Mechanistic studies revealed that resistance to cell death in PELP1-depleted cells upon genotoxic stress was due to significant decrease in expression of p53 target genes. Furthermore, we demonstrated that PELP1 is phosphorylated at Serine 1033 upon DNA damage. Using a novel phospho-specific PELP1 antibody that specifically recognizes phosphorylated Serine 1033 on PELP1, we show that various genomic insults can induce PELP1 phosphorylation in vivo. Using cell lines that are either proficient or deficient in DDR kinases like ATM, ATR or DNAPKc, we have also established that PELP1 is phosphorylated by all three kinases depending on the type of DNA damage. Interestingly, we also found that the phosphorylation of PELP1 at Ser-1033 is important for optimal p53's transcriptional functions and that the phosphorylated form of PELP1 is recruited to the site of DNA damage when analyzed by laser micro-irradiation and confocal imaging, suggesting a potential role of PELP1 in the DNA repair process. Overall, these studies established a previously uncharacterized role of PELP1 in DNA damage response. Since PELP1 is as proto-oncogene with deregulated expression in many cancers, these findings will have implications in our understanding of cancer progression and therapy.

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 2135. doi:1538-7445.AM2012-2135