Abstract
BackgroundRecently, we showed that PARP1 is involved in cotranscriptional splicing, possibly by bridging chromatin to RNA and recruiting splicing factors. It also can influence alternative splicing decisions through the regulation of RNAPII elongation. In this study, we investigated the effect of PARP1-mediated chromatin changes on RNAPII movement, during transcription and alternative splicing.ResultsWe show that RNAPII pauses at PARP1–chromatin structures within the gene body. Knockdown of PARP1 abolishes this RNAPII pausing, suggesting that PARP1 may regulate RNAPII elongation. Additionally, PARP1 alters nucleosome deposition and histone post-translational modifications at specific exon–intron boundaries, thereby affecting RNAPII movement. Lastly, genome-wide analyses confirmed that PARP1 influences changes in RNAPII elongation by either reducing or increasing the rate of RNAPII elongation depending on the chromatin context.ConclusionsThese studies suggest a context-specific effect of PARP1–chromatin binding on RNA polymerase movement and provide a platform to delineate PARP1’s role in RNA biogenesis and processing.
Highlights
poly [ADP-ribose] polymerase 1 (PARP1) known as ARDT1 belongs to family of proteins known as ADP-ribosylases
PARP1 is involved in mRNA splicing We previously showed that PARP1 KD in Drosophila S2 cells results in changes in alternative splicing of several genes [5]
We chose to analyze this mechanism in depth at two genes—AKAP200 and CAPER—because we found that (1) PARP1 binds to nucleosomes within their gene bodies and (2) PARP1 depletion correlated with changes in the splicing decisions observed through RNA-seq genomewide analyses [5] (Fig. 1a)
Summary
PARP1 known as ARDT1 belongs to family of proteins known as ADP-ribosylases This group of enzymes, up to 17 in humans, have varying degrees of homology but a highly conserved PARP catalytic domain. These proteins use NAD+ as a substrate to catalyze the addition of ADP-ribose moiety(ies) onto target proteins, the name ADP-ribosyltransferase. PARP1 is well known for its role in DNA-repair, genome integrity, and cell death [1] It adds poly-ADP-ribose (PAR) onto several proteins involved in NAD+ metabolism [2]. We showed that PARP1 is involved in cotranscriptional splicing, possibly by bridging chroma‐ tin to RNA and recruiting splicing factors It can influence alternative splicing decisions through the regulation of RNAPII elongation. We investigated the effect of PARP1-mediated chromatin changes on RNAPII move‐ ment, during transcription and alternative splicing
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