Abstract
ADP-ribosylation is a widespread posttranslational modification that is of particular therapeutic relevance due to its involvement in DNA repair. In response to DNA damage, PARP1 and 2 are the main enzymes that catalyze ADP-ribosylation at damage sites. Recently, serine was identified as the primary amino acid acceptor of the ADP-ribosyl moiety following DNA damage and appears to act as seed for chain elongation in this context. Serine-ADP-ribosylation strictly depends on HPF1, an auxiliary factor of PARP1/2, which facilitates this modification by completing the PARP1/2 active site. The signal is terminated by initial poly(ADP-ribose) chain degradation, primarily carried out by PARG, while another enzyme, (ADP-ribosyl)hydrolase 3 (ARH3), specifically cleaves the terminal seryl-ADP-ribosyl bond, thus completing the chain degradation initiated by PARG. This review summarizes recent findings in the field of serine-ADP-ribosylation, its mechanisms, possible functions and potential for therapeutic targeting through HPF1 and ARH3 inhibition.
Highlights
ADP-ribosylation refers to the transfer of ADP-ribose (ADPr) moiety from NAD+ onto substrate proteins or nucleic acids by enzymes termed (ADP-ribosyl)transferases (ARTs; Figure 1; Liu and Yu, 2015; Wei and Yu, 2016; Munnur and Ahel, 2017; Zarkovic et al, 2018; Munnur et al, 2019; Groslambert et al, 2021)
This review focuses on Ser-ADPr as the most prominent protein ADP-ribosylation type of the DNA damage response (DDR) and explains the details of its synthesis and removal, influence on cellular outcomes of DNA damage and the therapeutic potential of targeting Ser-ADPr signaling
The Histone PARylation Factor 1 (HPF1):PARP1 or 2 (PARP1/2) complex contains a putative peptide-binding cleft with a strong negative charge provided by HPF1 (Suskiewicz et al, 2020), which was suggested to explain the abundance of Ser-ADPr within lysine-serine (KS) consensus motifs (Leidecker et al, 2016; Bonfiglio et al, 2017)
Summary
ADP-ribosylation refers to the transfer of ADP-ribose (ADPr) moiety from NAD+ onto substrate proteins or nucleic acids by enzymes termed (ADP-ribosyl)transferases (ARTs; Figure 1; Liu and Yu, 2015; Wei and Yu, 2016; Munnur and Ahel, 2017; Zarkovic et al, 2018; Munnur et al, 2019; Groslambert et al, 2021). Serine-ADP-Ribosylation: Synthesis and Reversal latter, termed DNA repair PARPs, are activated by binding to DNA lesions and subsequently ADP-ribosylate a variety of different targets within the vicinity of the damage site (Langelier et al, 2012; Eustermann et al, 2015; Pascal, 2018).
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