Involvement of PARP1 in the regulation of alternative splicing

Abstract

Specialized chromatin structures such as nucleosomes with specific histone modifications decorate exons in eukaryotic genomes, suggesting a functional connection between chromatin organization and the regulation of pre-mRNA splicing. Through profiling the functional location of Poly (ADP) ribose polymerase, we observed that it is associated with the nucleosomes at exon/intron boundaries of specific genes, suggestive of a role for this enzyme in alternative splicing. Poly (ADP) ribose polymerase has previously been implicated in the PARylation of splicing factors as well as regulation of the histone modification H3K4me3, a mark critical for co-transcriptional splicing. In light of these studies, we hypothesized that interaction of the chromatin-modifying factor, Poly (ADP) ribose polymerase with nucleosomal structures at exon–intron boundaries, might regulate pre-mRNA splicing. Using genome-wide approaches validated by gene-specific assays, we show that depletion of PARP1 or inhibition of its PARylation activity results in changes in alternative splicing of a specific subset of genes. Furthermore, we observed that PARP1 bound to RNA, splicing factors and chromatin, suggesting that Poly (ADP) ribose polymerase serves as a gene regulatory hub to facilitate co-transcriptional splicing. These studies add another function to the multi-functional protein, Poly (ADP) ribose polymerase, and provide a platform for further investigation of this protein’s function in organizing chromatin during gene regulatory processes.

An Integrated Chemical Proteomics Approach for Quantitative Profiling of Intracellular ADP-Ribosylation

“…As an example application, we utilised this methodology to elucidate the first direct and quantitative comparison between the intracellular response in ADP-ribosylation to two clinical PARP inhibitors, Olaparib and Rucaparib. Our findings are in agreement with the recent reports that indicate pivotal functional roles of PARylation in mRNA splicing and modulation of RNAs 25,26,27,28,29 . This finding is further supported by a recent CRISPR screen that identified several high-confidence mRNA splicing factors, including DDX46 and SRSF11 (lower left quadrant in Figure 4A) which resulted in increased sensitivity to the PARP inhibitor Olaparib across several cell lines when mutated 30 .…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…PARP9 and PARP10 both modulate transcription and participate in the DNA damage response (103)(104)(105). A role for PARP1 in cotranscriptional gene splicing has been identified (33).…”

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

“…One possible mechanism by which iAs influences AS may be through an inhibition of DNA binding by alternative splicing regulators such as CCCTC-binding factor (CTCF) and poly (ADP) ribose polymerase (PARP1) (132,137,138). Interestingly, PARP1 co-localizes with CTCF on chromatin; this complex, with CTCF-dependent automodification of PARP1, permits PARylation activity in the absence of DNA damage (137,139).…”

“…Interestingly, PARP1 co-localizes with CTCF on chromatin; this complex, with CTCF-dependent automodification of PARP1, permits PARylation activity in the absence of DNA damage (137,139). Importantly, many splicing factors are regulated by PARylation (140)(141)(142)(143)(144) and any iAs-mediated inhibition of PARP1 binding to DNA not only affects the structural properties of chromatin but also the PARylation activities, which indirectly affect splicing decisions.…”