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

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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.