Grant: Discovery Grants Program - Individual

Introduction: The integrity of the genome is continuously challenged by various endogenous and exogenous factors that lead to DNA lesions. Therefore, repair and preservation of the genome is a prerequisite for normal cellular function and transmission of the genome to successive progeny. Organisms have evolved sophisticated molecular networks that recognize, signal, and repair DNA lesions, collectively referred to as the DNA damage response (DDR). Therefore, the basal rate of DNA damage is counteracted by DNA repair mechanisms that ensure that DNA damage is efficiently repaired. The overall goal of my research program is to understand the molecular mechanisms and signaling complexes that contribute to the DDR in human cells. The molecular mechanisms involved in the DDR are complex and cell-type specific, and further research is needed to comprehensively understand the full repertoire of molecular networks that drive DNA repair. Long non-coding RNAs (lncRNAs) constitute an important group of cellular molecules with various biological activities. The human genome contains 96,308 lncRNA genes, however only limited lncRNAs have been associated with biological functions. Recent studies demonstrate that lncRNA expression is increased in the presence of DNA damaging insults. Although certain lncRNAs have been linked with DDR networks, further research is required to better understand the role of lncRNAs in the DDR. Hypothesis and objectives: The overall aim of this research proposal is to investigate the role of lncRNAs in the DDR. I hypothesize that lncRNAs play an integral role in modulating the DDR, and differences in lncRNA expression may be an underlying molecular mechanism that contributes to cell-type specific DDRs. Three main objectives will be examined: (1) to identify cell-specific and sex-specific DNA damage responsive lncRNAs, (2) to develop an inducible and targeted DNA strand-break system to elucidate lncRNAs that are specifically responsive to DNA single strand breaks (SSBs) and double strand breaks (DSBs), and (3) to characterize the molecular function of DNA damage responsive lncRNAs in DDR signaling. Significance: LncRNAs are an emerging class of biomolecules and its cellular and molecular functions are still largely uncharacterized. DDR is complex and despite the plethora of research conducted to date on DDR signaling, the molecular mechanisms underlying cell-type and sex-specific DDR signaling networks have not been fully established. Moreover, a comprehensive analysis of DNA damage responsive lncRNAs, and how these lncRNAs modulates DDR have not been established. This research proposal will substantially contribute to enhancing the knowledge gap in DDR biology and further progress our understanding of the biological significance of lncRNAs. Overall, this study is expected to establish the role of lncRNA in our understanding of fundamental processes that regulate the integrity of the genome.