Abstract PR03: A lncRNA regulates DNA repair by homologous recombination

Abstract

Abstract Introduction: Long non-coding RNAs (lncRNAs) have been shown to contribute to DNA damage response (DDR) by regulating gene expression. However, very little is known about the role that lncRNAs play in regulating DNA repair. In this study we characterized a lncRNA that regulates DNA repair by Homologous recombination (HR) by modulating recruitment of DNA repair factors at the sites of DNA damage. Experimental procedures: Control or DNA damage treated cells were processed for gene expression analysis, qPCR, live cell imaging, Immunochemistry, Western blotting, FISH and RNA Immunoprecipitation. Results: Using a genome-wide microarray screen we identified a novel ubiquitously expressed lncRNA, DDSR1 (DNA damage-sensitive RNA 1), which is induced upon DNA damage by several DNA double-strand break (DSB) agents. DDSR1 induction upon DNA damage is dependent on the ATM-NF-kB pathway. Loss of DDSR1 impairs cell proliferation, DDR signaling and reduces DNA repair capacity by homologous recombination (HR). The HR defect upon DDSR1 knockdown is characterized by aberrant BRCA1 and RAP80 accumulation at DSB sites. DDSR1 interacts with hnRNPUL1, an RNA-binding protein involved in HR. Loss of hnRNPUL1 also results in aberrant BRCA1 and RAP80 recruitment at DSB sites. Our results indicate that DDSR1/hnRNPUL1 depletion results in HR inhibition due to reduced end resection caused by aberrant BRCA1 and RAP80 at DSBs. Conclusions: Our results reveal a previously unknown lncRNA involved in regulation of DDR by contributing DNA repair by HR. Our findings highlight the importance of DDSR1 in maintaining genome stability. Citation Format: Vivek Sharma, Simran Khurana, Nard Kubben, Kotb Abdelmohsen, Philipp Oberdoerffer, Myriam Gorospe, Tom Misteli. A lncRNA regulates DNA repair by homologous recombination. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr PR03.