Abstract
Transcription is a multistep, tightly regulated process. During transcription initiation, promoter recognition and pre-initiation complex (PIC) formation take place, in which dynamic recruitment or exchange of transcription activators occur. The precise coordination of the recruitment and removal of transcription factors, as well as chromatin structural changes, are mediated by post-translational modifications (PTMs). Poly(ADP-ribose) polymerases (PARPs) are key players in this process, since they can modulate DNA-binding activities of specific transcription factors through poly-ADP-ribosylation (PARylation). PARylation can regulate the transcription at three different levels: (1) by directly affecting the recruitment of specific transcription factors, (2) by triggering chromatin structural changes during initiation and as a response to cellular stresses, or (3) by post-transcriptionally modulating the stability and degradation of specific mRNAs. In this review, we principally focus on these steps and summarise the recent findings, demonstrating the mechanisms through which PARylation plays a potential regulatory role during transcription and DNA repair.
Highlights
The Mechanism of Poly-ADP-Ribosylation and the PARP SuperfamilyPARylation is a reversible post-translational modification (PTM), in which writers, such as poly(ADP-ribose) polymerases (PARPs) as well as erasers, including poly(ADP-ribose) glycohydrolases (PARGs) and ADP-ribosyl hydrolase 3 (ARH3) are involved [1,2,3,4,5,6,7]
PARP1 facilitates the recruitment of the SWItch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5/SNF2H) to the sites of DNA damage and promotes the interaction between SMARCA5 and ADP-ribosylated ring finger protein 168 (RNF168) (Figure 4B) [100]
We address the role of PARylation to understand their function during the transcription-coupled cellular responses
Summary
PARylation is a reversible post-translational modification (PTM), in which writers, such as poly(ADP-ribose) polymerases (PARPs) as well as erasers, including poly(ADP-ribose) glycohydrolases (PARGs) and ADP-ribosyl hydrolase 3 (ARH3) are involved [1,2,3,4,5,6,7]. ADP-ribosylation is a multistep process, involving initiation, elongation, branching, and the release of PAR units. PARP binds to nicotinamide adenine dinucleotide (NAD+ ) and cleaves the nicotine amid unit, catalysing the transfer of the ADP-ribose moieties to the acceptor protein [9]. PARPs are classified based on their enzymatic activity: PARP1, PARP2, PARP5a, and PARP5b catalyse PAR chain formation, while PARPs 3, 4, 6–8, 10–12, and 14–16 have been described as mono-ADP-ribosyl transferases (MARTs) [9]. Since PARylation is a reversible process, the covalently-attached PAR can be removed by PARGs and ARH3 as well, keeping the PAR levels in the cell under control. Cancers 2020, 12, 183 can efficiently cleave the PAR O-glycosidic bond, ARH3 is mainly responsible for the hydrolysis of protein-free PAR [11]
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