Abstract 3452: hnRNPUL1 regulation by ATR in DNA damage response

Abstract

Abstract The DNA damage response (DDR) is a signaling network that recognizes damages to DNA and orchestrates a variety of DNA repair and cell cycle checkpoint pathways. The DDR is pivotal for cancer prevention. Ataxia Telangiectasia And Rad3-Related Protein (ATR), a protein kinase, functions as an essential transducer of the DDR signaling cascade. ATR primarily responds to single-stranded DNA (ssDNA) generated from double-strand break resection or at stalled replication forks. Depletion of ATR leads to cellular senescence and cancer related phenotypes. The mechanisms regarding how the ATR signal pathway is regulated, however, remain elusive. To discover novel DDR proteins regulated by ATR, we performed proteomic analysis to identify proteins that partner with ATR in response to DNA damage in cells. Our analysis revealed a network of proteins as potential ATR substrates, including Heterogeneous nuclear ribonucleoprotein U-like 1 (hnRPUL1), a protein functions in RNA metabolism. We validated that ATR interacts with hnRNPUL1. In addition, hnRPUL1 is phosphorylated on SQ/TQ sites in response to IR. ATR depletion suppresses the IR induced hnRPUL1 phosphorylation. Our results identify hnRNPUL1 as a novel ATR substrate, critical for the DNA damage response and provide insight into how DDR and RNA metabolism might work synergically in maintaining genomic stability and preventing cancer. Additionally, hnRNPUL1 phosphorylation by ATR may be targeted as an adjunct to improve the efficacy of ionizing radiation for cancer therapy. Citation Format: Hui Zhang, PamelaSara E. Head, Duc M. Duong, Nicholas T. Seyfried, David S. Yu. hnRNPUL1 regulation by ATR in DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3452.