Elucidating the role of long non-coding RNA (lncRNA) in the DNA damage response

基因组的完整性不断受到各种内源性和外源性因素的挑战，导致DNA损伤。因此，修复和保存基因组是正常细胞功能和将基因组传递给后代的先决条件。生物体已经进化出复杂的分子网络，可以识别、发出信号并修复DNA损伤，统称为DNA损伤反应（DDR）。因此，DNA损伤的基本速率被DNA修复机制抵消，从而确保DNA损伤得到有效修复。我的研究计划的总体目标是了解分子机制和信号复合物，有助于在人类细胞中的DDR。DDR所涉及的分子机制是复杂的和细胞类型特异性的，需要进一步的研究来全面了解驱动DNA修复的分子网络的全部功能。长链非编码rna （Long non-coding rna, lncRNAs）是一类重要的细胞分子，具有多种生物活性。人类基因组包含96308个lncRNA基因，但只有有限的lncRNA与生物学功能相关。最近的研究表明，lncRNA的表达在DNA损伤中增加。虽然某些lncrna与DDR网络有关，但需要进一步研究以更好地了解lncrna在DDR中的作用。假设和目标：本研究计划的总体目的是研究lncrna在DDR中的作用。我假设lncRNA在调节DDR中起着不可或缺的作用，lncRNA表达的差异可能是导致细胞类型特异性DDR的潜在分子机制。将研究三个主要目标：(1)鉴定细胞特异性和性别特异性DNA损伤反应性lncrna，(2)开发一个可诱导和靶向的DNA链断裂系统，以阐明对DNA单链断裂（SSBs）和双链断裂（DSBs）特异性反应的lncrna，以及(3)表征DNA损伤反应性lncrna在DDR信号传导中的分子功能。意义：LncRNAs是一类新兴的生物分子，其细胞和分子功能在很大程度上仍未被明确。DDR是复杂的，尽管迄今为止对DDR信号传导进行了大量研究，但细胞类型和性别特异性DDR信号网络的分子机制尚未完全建立。此外，对DNA损伤反应性lncrna的全面分析以及这些lncrna如何调节DDR尚未建立。本研究计划将大大有助于填补DDR生物学的知识缺口，进一步加深我们对lncrna生物学意义的认识。总的来说，这项研究有望确立lncRNA在我们对调节基因组完整性的基本过程的理解中的作用。

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.