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.

简介：基因组的完整性不断受到导致DNA损伤的各种内源性和外源性因素的挑战，因此，基因组的修复和保存是正常细胞功能和基因组传递给后代的先决条件。识别、发出信号并修复 DNA 损伤的分子网络，统称为 DNA 损伤反应 (DDR)，因此，DNA 损伤的基础率通过 DNA 修复机制来抵消，以确保 DNA 损伤得到有效修复。我的研究该计划的目的是了解人类细胞中 DDR 的分子机制和信号复合物。 DDR 涉及的分子机制非常复杂且具有细胞类型特异性，需要进一步的研究来全面了解驱动分子网络的全部功能。 DNA 修复。长非编码 RNA (lncRNA) 是一组具有多种生物活性的重要细胞分子，但最近的研究表明，只有有限的 lncRNA 与生物功能相关。尽管某些 lncRNA 已与 DDR 网络相关，但 lncRNA 表达会增加，以更好地了解 lncRNA 在 DDR 中的作用。 假设和目标：本研究提案的总体目标是。为了研究lncRNA在DDR中的作用，我认为lncRNA在调节DDR中发挥着不可或缺的作用，并且lncRNA表达的差异可能是导致细胞类型特异性的潜在分子机制。将研究 DDR 的三个主要目标：(1) 识别细胞特异性和性别特异性 DNA 损伤响应性 lncRNA，(2) 开发诱导型和靶向 DNA 链断裂系统，以阐明对 DNA 单链特异性响应的 lncRNA。链断裂 (SSB) 和双链断裂 (DSB)，以及 (3) 表征 DDR 信号传导中 DNA 损伤响应性 lncRNA 的分子功能 意义：LncRNA 是一类新兴的类别。生物分子及其细胞和分子功能在很大程度上仍未得到表征，DDR 很复杂，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 信号传导网络的分子机制尚未完全建立。对 DNA 损伤响应性 lncRNA 以及这些 lncRNA 如何调节 DDR 的全面分析尚未建立，这项研究提案将大大有助于扩大 DDR 生物学的知识差距，并进一步增进我们对 DDR 生物学意义的理解。总的来说，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。