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

PARP 1（poly-ADP-ribose polymerase）是一种染色质结合蛋白，通过调节增殖、分化和衰老来维持哺乳动物基因组的完整性。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。最近的研究表明，转录和剪接是共同调节的，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，以DNA修复而闻名的PARP 1也调节选择性剪接。本项目旨在了解PARP 1-染色质复合物如何协调RNA聚合酶II（RNAPII）延伸，RNA和剪接因子来调节共转录剪接。这些结果将提供对PARP 1功能的深入了解，特别是在RNA生物合成中。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。外联活动将包括指导当地和区域小型学院的研究生，以及美国少数民族服务机构的早期职业教师，作为肯塔基州大学独特的指导计划的一部分。缺乏PARP 1如何调节共转录剪接的机制细节。该研究项目将测试PARP 1以两种非相互排斥的方式调节共转录剪接的假设：i）作为一种衔接子，将剪接因子招募到RNA中;和/或ii）以影响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被应用于绘制PARP 1-RNA-染色质的遗传和生化相互作用。这些研究将提供关于PARP 1在选择性剪接中的这种新鉴定的活性的重要新知识。此外，委员会认为，本项目由生物科学理事会分子和细胞生物科学部遗传机制项目和刺激竞争性研究既定计划（EPSCoR）联合资助，旨在阐明PARP 1调节染色质以调节选择性剪接和RNA加工的机制，为深入了解染色质结构在真核生物基因调控中的复杂作用提供基础。该奖项反映了NSF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。

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.