Full Text:   <1704>

Summary:  <1268>

CLC number: 

On-line Access: 2021-01-15

Received: 2020-05-08

Revision Accepted: 2020-08-10

Crosschecked: 2020-12-10

Cited: 0

Clicked: 3155

Citations:  Bibtex RefMan EndNote GB/T7714


Xiuhua LIU


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.1 P.21-30


ADP-ribosylhydrolases: from DNA damage repair to COVID-19

Author(s):  Lily YU, Xiuhua LIU, Xiaochun YU

Affiliation(s):  Westridge School, Pasadena, California 91105, USA; more

Corresponding email(s):   yuxiaochun@westlake.edu.cn, liuxiuhua_2004@163.com

Key Words:  DNA damage repair, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Adenosine diphosphate (ADP)-ribosylation, Macrodomain, ADP-ribosylhydrolase, deADP-ribosylation

Lily YU, Xiuhua LIU, Xiaochun YU. ADP-ribosylhydrolases: from DNA damage repair to COVID-19[J]. Journal of Zhejiang University Science B, 2021, 22(1): 21-30.

@article{title="ADP-ribosylhydrolases: from DNA damage repair to COVID-19",
author="Lily YU, Xiuhua LIU, Xiaochun YU",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T ADP-ribosylhydrolases: from DNA damage repair to COVID-19
%A Lily YU
%A Xiuhua LIU
%A Xiaochun YU
%J Journal of Zhejiang University SCIENCE B
%V 22
%N 1
%P 21-30
%@ 1673-1581
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000319

T1 - ADP-ribosylhydrolases: from DNA damage repair to COVID-19
A1 - Lily YU
A1 - Xiuhua LIU
A1 - Xiaochun YU
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 1
SP - 21
EP - 30
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000319

adenosine diphosphate (ADP)-ribosylation is a unique post-translational modification that regulates many biological processes, such as DNA damage repair. During DNA repair, ADP-ribosylation needs to be reversed by ADP-ribosylhydrolases. A group of ADP-ribosylhydrolases have a catalytic domain, namely the macrodomain, which is conserved in evolution from prokaryotes to humans. Not all macrodomains remove ADP-ribosylation. One set of macrodomains loses enzymatic activity and only binds to ADP-ribose (ADPR). Here, we summarize the biological functions of these macrodomains in DNA damage repair and compare the structure of enzymatically active and inactive macrodomains. Moreover, small molecular inhibitors have been developed that target macrodomains to suppress DNA damage repair and tumor growth. macrodomain proteins are also expressed in pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, these domains may not be directly involved in DNA damage repair in the hosts or pathogens. Instead, they play key roles in pathogen replication. Thus, by targeting macrodomains it may be possible to treat pathogen-induced diseases, such as coronavirus disease 2019 (COVID-19).




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]AhelD, Ho艡ej拧铆Z, WiechensN, et al., 2009. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science, 325(5945):1240-1243.

[2]Am茅JC, SpenlehauerC, de MurciaG, 2004. The PARP superfamily. BioEssays, 26(8):882-893.

[3]Am茅JC, FouquerelE, GauthierLR, et al., 2009. Radiation-induced mitotic catastrophe in PARG-deficient cells. J Cell Sci, 122(Pt 12):1990-2002.

[4]AudehMW, CarmichaelJ, PensonRT, et al., 2010. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet, 376(9737):245-251.

[5]BarkauskaiteE, BrassingtonA, TanES, et al., 2013. Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities. Nat Commun, 4:2164.

[6]BarkauskaiteE, JankeviciusG, AhelI, 2015. Structures and mechanisms of enzymes employed in the synthesis and degradation of PARP-dependent protein ADP-ribosylation. Mol Cell, 58(6):935-946.

[7]BenekeS, DiefenbachJ, B眉rkleA, 2004. Poly(ADP-ribosyl)ation inhibitors: promising drug candidates for a wide variety of pathophysiologic conditions. Int J Cancer, 111(6):813-818.

[8]BryantHE, SchultzN, ThomasHD, et al., 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 434(7035):913-917.

[9]B眉tepageM, EckeiL, VerheugdP, et al., 2015. Intracellular mono-ADP-ribosylation in signaling and disease. Cells, 4(4):569-595.

[10]B眉tepageM, PreisingerC, von KriegsheimA, et al., 2018. Nucleolar-nucleoplasmic shuttling of TARG1 and its control by DNA damage-induced poly-ADP-ribosylation and by nucleolar transcription. Sci Rep, 8:6748.

[11]ChenDW, VollmarM, RossiMN, et al., 2011. Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases. J Biol Chem, 286(15):13261-13271.

[12]ChenSH, YuXC, 2019. Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies. Sci Adv, 5(4):eaav4340.

[13]DaughertyMD, YoungJM, KernsJA, et al., 2014. Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLoS Genet, 10(5):e1004403.

[14]EgloffMP, MaletH, PuticsA, et al., 2006. Structural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. J Virol, 80(17):8493-8502.

[15]FauzeeNJS, PanJ, WangYL, 2010. PARP and PARG inhibitors鈥攏ew therapeutic targets in cancer treatment. Pathol Oncol Res, 16(4):469-478.

[16]FehrAR, JankeviciusG, AhelI, et al., 2018. Viral macrodomains: unique mediators of viral replication and pathogenesis. Trends Microbiol, 26(7):598-610.

[17]FeijsKLH, ForstAH, VerheugdP, et al., 2013. Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation. Nat Rev Mol Cell Biol, 14(7):443-451.

[18]FeijsKLH, CooperCDO, 沤ajaR, 2020. The controversial roles of ADP-ribosyl hydrolases MACROD1, MACROD2 and TARG1 in carcinogenesis. Cancers (Basel), 12(3):604.

[19]FisherAEO, HocheggerH, TakedaS, et al., 2007. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol Cell Biol, 27(15):5597-5605.

[20]GarufiG, PalazzoA, ParisI, et al., 2020. Neoadjuvant therapy for triple-negative breast cancer: potential predictive biomarkers of activity and efficacy of platinum chemotherapy, PARP- and immune-checkpoint-inhibitors. Expert Opin Pharmacother, 21(6):687-699.

[21]GogolaE, DuarteAA, de RuiterJR, et al., 2019. Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell, 35(6):950-952.

[22]GoliaB, MoellerGK, JankeviciusG, et al., 2017. ATM induces MacroD2 nuclear export upon DNA damage. Nucleic Acids Res, 45(1):244-254.

[23]GorbalenyaAE, EnjuanesL, ZiebuhrJ, et al., 2006. Nidovirales: evolving the largest RNA virus genome. Virus Res, 117(1):17-37.

[24]GrundyGJ, RultenSL, ZengZH, et al., 2013. APLF promotes the assembly and activity of non-homologous end joining protein complexes. EMBO J, 32(1):112-125.

[25]HasslerM, JankeviciusG, LadurnerAG, 2011. PARG: a macrodomain in disguise. Structure, 19(10):1351-1353.

[26]HoulJH, YeZ, BroseyCA, et al., 2019. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death. Nat Commun, 10:5654.

[27]JankeviciusG, HasslerM, GoliaB, et al., 2013. A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nat Struct Mol Biol, 20(4):508-514.

[28]JankeviciusG, ArizaA, AhelM, et al., 2016. The toxin-antitoxin system DarTG catalyzes reversible ADP-ribosylation of DNA. Mol Cell, 64(6):1109-1116.

[29]KassabMA, YuXC, 2019. The role of dePARylation in DNA damage repair and cancer suppression. DNA Repair (Amst), 76:20-29

[30]KassabMA, YuLL, YuXC, 2020. Targeting dePARylation for cancer therapy. Cell Biosci, 10:7.

[31]KaufmannT, GrishkovskayaI, PolyanskyAA, et al., 2017. A novel non-canonical PIP-box mediates PARG interaction with PCNA. Nucleic Acids Res, 45(16):9741-9759.

[32]KleineH, PorebaE, LesniewiczK, et al., 2008. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol Cell, 32(1):57-69.

[33]KowieskiTM, LeeS, DenuJM, 2008. Acetylation-dependent ADP-ribosylation by Trypanosoma brucei Sir2. J Biol Chem, 283(9):5317-5326.

[34]KozlowskiM, CorujoD, HothornM, et al., 2018. MacroH2A histone variants limit chromatin plasticity through two distinct mechanisms. EMBO Rep, 19(10):e44445.

[35]KrietschJ, RouleauM, 脡Pic, et al., 2013. Reprogramming cellular events by poly(ADP-ribose)-binding proteins. Mol Aspects Med, 34(6):1066-1087.

[36]KustatscherG, HothornM, PugieuxC, et al., 2005. Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol, 12(7):624-625.

[37]LambrechtMJ, BrichacekM, BarkauskaiteE, et al., 2015. Synthesis of dimeric ADP-ribose and its structure with human poly(ADP-ribose) glycohydrolase. J Am Chem Soc, 137(10):3558-3564.

[38]LaStarzaMW, LemmJA, RiceCM, 1994. Genetic analysis of the nsP3 region of sindbis virus: evidence for roles in minus-strand and subgenomic RNA synthesis. J Virol, 68(9):5781-5791.

[39]LeungAKL, McPhersonRL, GriffinDE, 2018. Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases. PLoS Pathog, 14(3):e1006864.

[40]LiM, YuX, 2015. The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy. Oncogene, 34(26):3349-3356.

[41]LiuC, VyasA, KassabMA, et al., 2017. The role of poly ADP-ribosylation in the first wave of DNA damage response. Nucleic Acids Res, 45(14):8129-8141.

[42]MaletH, DalleK, Br茅mondN, et al., 2006. Expression, purification and crystallization of the SARS-CoV macro domain. Acta Cryst Sect F Struct Biol Cryst Commun, 62(Pt 4):405-408.

[43]MaletH, CoutardB, JamalS, et al., 2009. The crystal structures of Chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. J Virol, 83(13):6534-6545.

[44]Marjanovi膰MP, Hurtado-Bag猫sS, LassiM, et al., 2017. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. Nat Struct Mol Biol, 24(11):902-910.

[45]MichelsJ, VitaleI, SaparbaevM, et al., 2014. Predictive biomarkers for cancer therapy with PARP inhibitors. Oncogene, 33(30):3894-3907.

[46]MinW, CortesU, HercegZ, et al., 2010. Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis. Carcinogenesis, 31(12):2058-2065.

[47]MunnurD, AhelI, 2017. Reversible mono-ADP-ribosylation of DNA breaks. FEBS J, 284(23):4002-4016.

[48]MunnurD, BartlettE, Mikol膷evi膰P, et al., 2019. Reversible ADP-ribosylation of RNA. Nucleic Acids Res, 47(11):5658-5669.

[49]NanYC, YuY, MaZX, et al., 2014. Hepatitis E virus inhibits type I interferon induction by ORF1 products. J Virol, 88(20):11924-11932.

[50]NeuvonenM, AholaT, 2009. Differential activities of cellular and viral macro domain proteins in binding of ADP-ribose metabolites. J Mol Biol, 385(1):212-225.

[51]PatelCN, KohDW, JacobsonMK, et al., 2005. Identification of three critical acidic residues of poly(ADP-ribose) glycohydrolase involved in catalysis: determining the PARG catalytic domain. Biochem J, 388(Pt 2):493-500.

[52]PerinaD, Miko膷A, AhelJ, et al., 2014. Distribution of protein poly(ADP-ribosyl)ation systems across all domains of life. DNA Repair (Amst), 23:4-16.

[53]PillayN, TigheA, NelsonL, et al., 2019. DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors. Cancer Cell, 35(3):519-533.e8.

[54]PoltronieriP, MiwaM, 2016. Editorial (thematic issue: overview on ADP ribosylation and PARP superfamily of proteins). Curr Protein Pept Sci, 17(7):630-632.

[55]PowellSN, KachnicLA, 2003. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene, 22(37):5784-5791.

[56]RackJGM, MorraR, BarkauskaiteE, et al., 2015. Identification of a class of protein ADP-ribosylating sirtuins in microbial pathogens. Mol Cell, 59(2):309-320.

[57]RackJGM, PerinaD, AhelI, 2016. Macrodomains: structure, function, evolution, and catalytic activities. Annu Rev Biochem, 85:431-454.

[58]RackJGM, PalazzoL, AhelI, 2020. (ADP-ribosyl)hydrolases: structure, function, and biology. Genes Dev, 34(5-6):263-284.

[59]RosenthalF, FeijsKLH, FrugierE, et al., 2013. Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases. Nat Struct Mol Biol, 20(4):502-507.

[60]RuizPD, HamiltonGA, ParkJW, et al., 2019. MacroH2A1 regulation of poly(ADP-ribose) synthesis and stability prevents necrosis and promotes DNA repair. Mol Cell Biol, 40(1):e00230-19.

[61]SharifiR, MorraR, AppelCD, et al., 2013. Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. EMBO J, 32(9):1225-1237.

[62]ShiraiH, PoetschAR, GunjiA, et al., 2013. PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways. Cell Death Dis, 4:e656.

[63]ShullNP, SpinelliSL, PhizickyEM, 2005. A highly specific phosphatase that acts on ADP-ribose 1"-phosphate, a metabolite of tRNA splicing in Saccharomyces cerevisiae. Nucleic Acids Res, 33(2):650-660.

[64]SimonNC, AktoriesK, BarbieriJT, 2014. Novel bacterial ADP-ribosylating toxins: structure and function. Nat Rev Microbiol, 12(9):599-611.

[65]SladeD, 2020. PARP and PARG inhibitors in cancer treatment. Genes Dev, 34(5-6):360-394.

[66]TalhaouiI, LebedevaNA, ZarkovicG, et al., 2016. Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro. Nucleic Acids Res, 44(19):9279-9295.

[67]TuckerJA, BennettN, BrassingtonC, et al., 2012. Structures of the human poly(ADP-ribose) glycohydrolase catalytic domain confirm catalytic mechanism and explain inhibition by ADP-HPD derivatives. PLoS ONE, 7(12):e50889.

[68]VyasS, MaticI, UchimaL, et al., 2014. Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun, 5:4426.

[69]WeiHT, YuXC, 2016. Functions of PARylation in DNA damage repair pathways. Genomics Proteomics Bioinformatics, 14(3):131-139.

[70]YangCS, JividenK, SpencerA, et al., 2017. Ubiquitin modification by the E3 ligase/ADP-ribosyltransferase Dtx3L/Parp9. Mol Cell, 66(4):503-516.e5.

[71]YangXY, MaYL, LiYM, et al., 2020. Molecular basis for the MacroD1-mediated hydrolysis of ADP-ribosylation. DNA Repair (Amst), 94:102899.

[72]YuM, SchreekS, CerniC, et al., 2005. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene, 24(12):1982-1993.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2023 Journal of Zhejiang University-SCIENCE