The multifaceted role of PARP1 in RNA biogenesis

Abstract

Poly(ADP‐ribose) polymerases (PARPs) are abundant nuclear proteins that synthesize ADP ribose polymers (pADPr) and catalyze the addition of (p)ADPr to target biomolecules. PARP1, the most abundant and well‐studied PARP, is a multifunctional enzyme that participates in numerous critical cellular processes. A considerable amount of PARP research has focused on PARP1's role in DNA damage. However, an increasing body of evidence outlines more routine roles for PARP and PARylation in nearly every step of RNA biogenesis and metabolism. PARP1's involvement in these RNA processes is pleiotropic and has been ascribed to PARP1's unique flexible domain structures. PARP1 domains are modular self‐arranged enabling it to recognize structurally diverse substrates and to act simultaneously through multiple discrete mechanisms. These mechanisms include direct PARP1‐protein binding, PARP1‐nucleic acid binding, covalent PARylation of target molecules, covalent autoPARylation, and induction of noncovalent interactions with PAR molecules. A combination of these mechanisms has been implicated in PARP1's context‐specific regulation of RNA biogenesis and metabolism. We examine the mechanisms of PARP1 regulation in transcription initiation, elongation and termination, co‐transcriptional splicing, RNA export, and post‐transcriptional RNA processing. Finally, we consider promising new investigative avenues for PARP1 involvement in these processes with an emphasis on PARP1 regulation of subcellular condensates. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing

CTCF as a regulator of alternative splicing: new tricks for an old player

“…A follow up study found that RNAPII elongation rate was also modulated at these sites depending on chromatin structure, which is disrupted upon PARP1 depletion ( 67 ). PARP1, in addition to its role as a PARylation activator, has been linked to regulation of transcription and AS via multiple mechanisms involving chromatin modulation, transcriptional modulation, post-transcriptional regulation of RNA-binding proteins and mRNA stabilization (reviewed in ( 68 , 69 )). While this is true, possible roles for CTCF in the regulation of AS via activating PARP1 and PARylation will reveal new aspects of AS regulatory mechanisms, which require further investigation (Figure 2B ).…”

“…Given its direct effect on PARP1 and its PARylation activity ( 60 , 61 ), CTCF might possibly regulate AS via RNA-binding proteins, whose binding, recruitment and expression are directly regulated by PARP1 and/or PARylation ( 68 ) (Figure 2B and C ). This could be tested by examining the effect of CTCF on PARP1-mediated recruitment of SF3B1 and subsequently pre-mRNA splicing ( 66 ).…”

Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

“…In the context of global BER/SSBR, CRISPR-mediated KO of PARP1 is shown to prevent the formation of BER/SSBR protein complexes at sites of laser-induced DNA damage [366]. Recent studies have also suggested a complicated role for PARP1 in RNA biology, a role for RNA in PARP1 activation, and possibly as a target of PARP1 activation [367][368][369][370][371][372][373]. Further, Krauss et al suggest the snoRNAs may be endogenous PARP1 activators, confirmed by creating CRISPR/Cas9-mediated KO of snoRNAs in cells [374].…”

Transcriptional Regulation of Inflammasomes

“…Poly(ADP-ribose) polymerase 1 (PARP-1) is one of the most abundant nuclear protein. PARP-1 is a multifunctional enzyme acting at numerous levels to regulate transcription [93]. Interestingly, Yoo et al identified that PARP-1 is necessary for LPS-induced, but not IFNγ-induced Cas-11 expression.…”