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

阐明长非编码 RNA (lncRNA) 在 DNA 损伤反应中的作用

• 批准号: RGPIN-2022-03159
• 负责人: Tharmalingam, Sujeenthar
• 金额: $ 2.04万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760903
• 关键词: Elucidating; role; long; non; coding

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.

前言：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，这些因素导致DNA损伤。因此，基因组的修复和保存是细胞正常功能和向后代传递基因组的先决条件。生物已经进化出复杂的分子网络，可以识别、发出信号和修复DNA损伤，统称为DNA损伤反应(DDR)。因此，DNA损伤的基本速率被确保DNA损伤得到有效修复的DNA修复机制所抵消。我的研究计划的总体目标是了解导致人类细胞DDR的分子机制和信号复合体。DDR涉及的分子机制复杂且具有细胞类型特异性，需要进一步研究才能全面了解驱动DNA修复的分子网络的全部内容。长非编码RNA(Long Non-Coding RNAs，LncRNAs)是一类具有多种生物学活性的重要细胞分子。人类基因组包含96,308个lncRNA基因，然而只有有限的lncRNA与生物功能相关。最近的研究表明，在DNA损伤的情况下，lncRNA的表达会增加。虽然某些LncRNAs已与复员方案网络联系在一起，但还需要进一步研究，以更好地了解LncRNAs在DDR中的作用。假设和目的：本研究提案的总体目的是研究lncRNAs在DDR中的作用。我推测，lncRNAs在调节DDR中起着不可或缺的作用，而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。主要目标有三个：(1)鉴定细胞特异性和性别特异性的DNA损伤反应基因；(2)建立一个可诱导的、靶向的DNA链断裂系统，以阐明对DNA单链断裂(SSB)和双链断裂(DSB)特异反应的LncRNAs；(3)研究DNA损伤反应基因在DDR信号中的分子功能。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确定。DDR是复杂的，尽管迄今为止对DDR信号进行了过多的研究，但细胞型和性别特异性DDR信号网络的分子机制尚未完全建立。此外，对DNA损伤反应的lncRNAs以及这些lncRNAs如何调节DDR的全面分析尚未建立。这项研究建议将大大有助于加强DDR生物学方面的知识差距，并进一步促进我们对lncRNAs生物学意义的理解。总体而言，这项研究有望确定lncRNA在我们理解调节基因组完整性的基本过程中的作用。