Functions of PARylation in DNA Damage Repair Pathways

Abstract

Protein poly ADP-ribosylation (PARylation) is a widespread post-translational modification at DNA lesions, which is catalyzed by poly(ADP-ribose) polymerases (PARPs). This modification regulates a number of biological processes including chromatin reorganization, DNA damage response (DDR), transcriptional regulation, apoptosis, and mitosis. PARP1, functioning as a DNA damage sensor, can be activated by DNA lesions, forming PAR chains that serve as a docking platform for DNA repair factors with high biochemical complexity. Here, we highlight molecular insights into PARylation recognition, the expanding role of PARylation in DDR pathways, and the functional interaction between PARylation and ubiquitination, which will offer us a better understanding of the biological roles of this unique post-translational modification.

Keywords: DNA damage response; PAR-binding modules; PARPs; Poly ADP-ribosylation; Ubiquitination.

Figure 1

PARylation mediates DNA damage repair The scheme depicts DNA repair networks regulated by PARylation. As might be expected, PARPs interact physically and functionally with several DNA damage factors to promote their recruitment to the sites of DNA damage. alt-NHEJ, alternative non-homologous end joining; APE, apurinic/apyrimidinic (AP) endonuclease; BER, base excision repair; BRCA1, breast cancer type 1 susceptibility protein; BRCA2, breast cancer type 2 susceptibility protein; C-NHEJ, classical non-homologous end joining; CtIP, C-terminal-binding protein (CtBP)-interacting protein; DNAP, DNA polymerase; DNA-PKcs, DNA-dependent protein kinase, catalytic subunit; FEN-1, flap structure-specific endonuclease 1; HR, homologous recombination; MRE11, meiotic recombination 11 homolog 1; MRN, Mre11-Rad50-Nbs1 complex; OGG-1, 8-oxoguanine glycosylase 1; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; RPA, replication protein A; SSBR, single-strand break repair; XRCC4, X-ray repair cross-complementing protein 4.

Figure 2

PAR-binding modules Using NAD⁺ as substrate, PARPs can produce PAR chain. For degradation, PARG and ARH3 mainly cleave the bonds of the PAR chain, except the proximal protein-bound ADP-ribose. The hydrolysis of last ADP-ribose from modified protein is conducted by TARG, MacroD1, and MacroD2. PBZ, WWE, Macro domain, FHA domain, OB-fold BRCT domain, RRM, and RGG motifs/domains can recognize the different parts of the PAR chain. ARH3, ADP-ribosylhydrolase 3; BRCT, BRCA1 C terminus; FHA, forkhead-associated; MacroD, Macro domain-containing protein; OB-fold, oligonucleotide/oligosaccharide-binding domain; PAR, poly(ADP ribose); PARG, PAR glycohydrolase; PARP, PAR polymerase; PBZ, PAR-binding zinc-finger; PIN, protein incorporated later into tight junctions (PilT) N terminus; RGG, arginine-glycine-glycine; RRM, RNA recognition motif; TARG, terminal ADP-ribose glycohydrolase; WWE, tryptophan-tryptophan-glutamate.