Role of poly(ADP-ribose) polymerase 1 in regulating RNA polymerase II elongation and mRNA splicing

聚（ADP-核糖）聚合酶 1 在调节 RNA 聚合酶 II 延伸和 mRNA 剪接中的作用

• 批准号: 2016515
• 负责人: Yvonne Fondufe-Mittendorf
• 金额: $ 78万
• 依托单位: University of Kentucky Research Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2016515&HistoricalAwards=false
• 关键词: Role; poly; ADP; ribose; polymerase

PARP1 (poly-ADP-ribose polymerase), a chromatin-binding protein, is crucial for maintaining genomic integrity in mammals through regulation of proliferation, differentiation and aging. Control of gene expression occurs at different levels – importantly, at transcription initiation and mRNA splicing. Recent studies show that transcription and splicing are co-regulated and that chromatin structure plays a key role in this process. In an earlier study, the research group found that PARP1, which is well known for DNA repair, also regulates alternative splicing. This project aims to understand how PARP1-chromatin complex coordinates RNA polymerase II (RNAPII) elongation, RNA, and splicing factors to regulate co-transcriptional splicing. The outcomes will provide insights into PARP1 function, especially in RNA biogenesis. The project will offer training opportunities for underrepresented high school and undergraduate students during summer months. Outreach activities will include mentoring graduate students at local and regional small colleges, as well as early career faculty at US minority-serving institutions as part of a unique University of Kentucky mentoring program. Mechanistic details of how PARP1 regulates co-transcriptional splicing are lacking. This research project will test the hypotheses that PARP1 regulates co-transcriptional splicing in two non-mutually exclusive ways: i) by acting as an adapter to recruit splicing factors to RNA; and/or ii) by modulating chromatin structure in ways that affect RNAPII elongation and kinetics. Large-scale genomics and gene-specific approaches will be applied to map the genetic and biochemical interactions of PARP1-RNA-chromatin. These studies will provide significant new knowledge about this newly identified activity of PARP1 in alternative splicing. Furthermore, deciphering the mechanism(s) by which PARP1 modulates chromatin to regulate alternative splicing and RNA processing will provide fundamental insights into the complex role of chromatin structure in eukaryotic gene regulation.This project is jointly funded by the Genetic Mechanisms program in the Molecular and Cellular Biosciences Division of the Biological Sciences Directorate and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PARP1 （poly- adp -核糖聚合酶）是一种染色质结合蛋白，通过调节哺乳动物的增殖、分化和衰老，对维持基因组完整性至关重要。基因表达的控制发生在不同的水平-重要的是，在转录起始和mRNA剪接。近年来的研究表明，转录和剪接是共同调控的，而染色质结构在这一过程中起着关键作用。在早期的一项研究中，研究小组发现，PARP1，众所周知的DNA修复，也调节选择性剪接。本项目旨在了解parp1 -染色质复合体如何协调RNA聚合酶II （RNAPII）延伸、RNA和剪接因子来调节共转录剪接。这些结果将为PARP1的功能，特别是RNA生物发生提供新的见解。该项目将在夏季为代表性不足的高中生和本科生提供培训机会。拓展活动将包括指导当地和地区小型学院的研究生，以及作为肯塔基大学独特指导计划的一部分，在美国少数民族服务机构的早期职业教师。目前还缺乏PARP1调控共转录剪接的机制细节。本研究项目将测试PARP1以两种非互斥方式调节共转录剪接的假设：i)作为适配器将剪接因子招募到RNA；和/或ii)通过影响RNAPII延伸和动力学的方式调节染色质结构。大规模基因组学和基因特异性方法将应用于绘制parp1 - rna -染色质的遗传和生化相互作用。这些研究将为新发现的PARP1在选择性剪接中的活性提供重要的新知识。此外，破译PARP1调节染色质调控选择性剪接和RNA加工的机制将为真核生物基因调控中染色质结构的复杂作用提供基础见解。该项目由生物科学理事会分子和细胞生物科学部的遗传机制计划和促进竞争性研究的既定计划（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。