The Making and Breaking of Serine-ADP-Ribosylation in the DNA Damage Response

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.

Keywords: ADP-ribosylation; ARH3; DNA damage; PARG; PARP; cancer; neurodegeneration; posttranslational modification (PTM).

FIGURE 1

Ser-ADPr is a reversible and complex modification. The reaction involves the transfer of the ADPr moiety from β-NAD⁺ under inversion at the anomeric carbon, thus resulting in a modification in the α-conformation. The initial modification of a serine residue is catalyzed by the PARP1/2:HPF1 complex (box 1), while further chain extension is catalyzed by PARP1/2 alone. The latter occurs as linear, ribose(1″→2′)ribose (box 2), or infrequently branched, ribose(1″→2″)ribose(1″→2′)ribose (box 3), continuations leading to a large and diverse polymer structure. Linear polymers are primarily degraded by PARG, and to a lesser extend ARH3, while branch pruning, hydrolysis of the 1″→2″ bond, is carried out solely by PARG and precedes the cleavage of the 1″→2′ bond at branch points. In contrast, the proximal seryl-ADP-ribosyl bond can only be cleaved by ARH3. Identified target proteins in the context of the DDR include PARP1 and 2 themselves (automodification), histones (primarily H2B, H3, H4, and H1), FEN1, LIG3, and NUCKS1.