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

PARP1(PolyADP核糖聚合酶)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，在转录启动和信使核糖核酸的剪接。最近的研究表明，转录和剪接是相互调控的，染色质结构在这一过程中起着关键作用。在之前的一项研究中，研究小组发现，以DNA修复闻名的PARP1也调节着选择性剪接。该项目旨在了解PARP1-染色质复合体如何协调RNA聚合酶II(RNAPII)的延伸、RNA和剪接因子来调节共转录剪接。这些结果将为PARP1的功能提供见解，特别是在RNA生物发生中。该项目将在夏季为未被充分代表的高中生和本科生提供培训机会。外展活动将包括指导当地和地区性小型学院的研究生，以及美国少数族裔服务机构的早期职业教师，这是肯塔基大学独特指导计划的一部分。PARP1如何调控共转录剪接的机制细节还缺乏。本研究项目将检验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。将应用大规模基因组学和基因特异性方法来绘制PARP1-RNA-染色质的遗传和生化相互作用图。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调节染色质以调节选择性剪接和RNA加工的机制(S)将为了解染色质结构在真核基因调控中的复杂作用提供基本的见解。该项目由生物科学局分子和细胞生物科学部门的遗传机制计划和既定的刺激竞争研究计划共同资助。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智力优势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.