XRCC1 Protects Transcription from Toxic PARP1 Activity During DNA Base Excision Repair

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2021 Nov 23

PMID 34811483

Citations 10

Authors

Marek Adamowicz

Richard Hailstone

Annie A Demin

Emilia Komulainen

Hana Hanzlikova

Jan Brazina

Amit Gautam

Sophie E Wells

Keith W Caldecott

Affiliations

Soon will be listed here.

Abstract

Genetic defects in the repair of DNA single-strand breaks (SSBs) can result in neurological disease triggered by toxic activity of the single-strand-break sensor protein PARP1. However, the mechanism(s) by which this toxic PARP1 activity triggers cellular dysfunction are unclear. Here we show that human cells lacking XRCC1 fail to rapidly recover transcription following DNA base damage, a phenotype also observed in patient-derived fibroblasts with XRCC1 mutations and Xrcc1 mouse neurons. This defect is caused by excessive/aberrant PARP1 activity during DNA base excision repair, resulting from the loss of PARP1 regulation by XRCC1. We show that aberrant PARP1 activity suppresses transcriptional recovery during base excision repair by promoting excessive recruitment and activity of the ubiquitin protease USP3, which as a result reduces the level of monoubiquitinated histones important for normal transcriptional regulation. Importantly, inhibition and/or deletion of PARP1 or USP3 restores transcriptional recovery in XRCC1 cells, highlighting PARP1 and USP3 as possible therapeutic targets in neurological disease.

Citing Articles

Redox regulation: mechanisms, biology and therapeutic targets in diseases.

Li B, Ming H, Qin S, Nice E, Dong J, Du Z Signal Transduct Target Ther. 2025; 10(1):72.

PMID: 40050273 PMC: 11885647. DOI: 10.1038/s41392-024-02095-6.

XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites.

Lin X, Leung K, Wolfe K, Call N, Bhandari S, Huang X Nucleic Acids Res. 2025; 53(4).

PMID: 39970298 PMC: 11838041. DOI: 10.1093/nar/gkaf086.

deletion rescues cerebellar hypotrophy in mutant zebrafish.

Semenova S, Nammi D, Garrett G, Margolin G, Sinclair J, Maroofian R bioRxiv. 2025; .

PMID: 39803460 PMC: 11722395. DOI: 10.1101/2024.11.25.625242.

DNA damage and its links to neuronal aging and degeneration.

Delint-Ramirez I, Madabhushi R Neuron. 2025; 113(1):7-28.

PMID: 39788088 PMC: 11832075. DOI: 10.1016/j.neuron.2024.12.001.

TRIM25-mediated XRCC1 ubiquitination accelerates atherosclerosis by inducing macrophage M1 polarization and programmed death.

Wu H, Gao W, Ma Y, Zhong X, Qian J, Huang D Inflamm Res. 2024; 73(9):1445-1458.

PMID: 38896288 DOI: 10.1007/s00011-024-01906-4.

References

Lindahl T . Instability and decay of the primary structure of DNA. Nature. 1993; 362(6422):709-15. DOI: 10.1038/362709a0. View

Yoon G, Caldecott K . Nonsyndromic cerebellar ataxias associated with disorders of DNA single-strand break repair. Handb Clin Neurol. 2018; 155:105-115. DOI: 10.1016/B978-0-444-64189-2.00007-X. View

McKinnon P . Genome integrity and disease prevention in the nervous system. Genes Dev. 2017; 31(12):1180-1194. PMC: 5558921. DOI: 10.1101/gad.301325.117. View

Caldecott K . Protein ADP-ribosylation and the cellular response to DNA strand breaks. DNA Repair (Amst). 2014; 19:108-13. DOI: 10.1016/j.dnarep.2014.03.021. View

Jungmichel S, Rosenthal F, Altmeyer M, Lukas J, Hottiger M, Nielsen M . Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses. Mol Cell. 2013; 52(2):272-85. DOI: 10.1016/j.molcel.2013.08.026. View

Ray Chaudhuri A, Nussenzweig A . The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017; 18(10):610-621. PMC: 6591728. DOI: 10.1038/nrm.2017.53. View

Satoh M, Lindahl T . Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992; 356(6367):356-8. DOI: 10.1038/356356a0. View

Hanzlikova H, Gittens W, Krejcikova K, Zeng Z, Caldecott K . Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin. Nucleic Acids Res. 2016; 45(5):2546-2557. PMC: 5389470. DOI: 10.1093/nar/gkw1246. View

Breslin C, Hornyak P, Ridley A, Rulten S, Hanzlikova H, Oliver A . The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function. Nucleic Acids Res. 2015; 43(14):6934-44. PMC: 4538820. DOI: 10.1093/nar/gkv623. View

10.

Masson M, Niedergang C, Schreiber V, Muller S, de Murcia G . XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol. 1998; 18(6):3563-71. PMC: 108937. DOI: 10.1128/MCB.18.6.3563. View

11.

Caldecott K, Aoufouchi S, Johnson P, Shall S . XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular 'nick-sensor' in vitro. Nucleic Acids Res. 1996; 24(22):4387-94. PMC: 146288. DOI: 10.1093/nar/24.22.4387. View

12.

Kubota Y, Nash R, Klungland A, Schar P, Barnes D, Lindahl T . Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. EMBO J. 1996; 15(23):6662-70. PMC: 452490. View

13.

Caldecott K, McKeown C, Tucker J, Ljungquist S, Thompson L . An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III. Mol Cell Biol. 1994; 14(1):68-76. PMC: 358357. DOI: 10.1128/mcb.14.1.68-76.1994. View

14.

Loizou J, El-Khamisy S, Zlatanou A, Moore D, Chan D, Qin J . The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks. Cell. 2004; 117(1):17-28. DOI: 10.1016/s0092-8674(04)00206-5. View

15.

Whitehouse C, Taylor R, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko D . XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell. 2001; 104(1):107-17. DOI: 10.1016/s0092-8674(01)00195-7. View

16.

Clements P, Breslin C, Deeks E, Byrd P, Ju L, Bieganowski P . The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair (Amst). 2004; 3(11):1493-502. DOI: 10.1016/j.dnarep.2004.06.017. View

17.

Luo H, Chan D, Yang T, Rodriguez M, Chen B, Leng M . A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment. Mol Cell Biol. 2004; 24(19):8356-65. PMC: 516742. DOI: 10.1128/MCB.24.19.8356-8365.2004. View

18.

Hoch N, Hanzlikova H, Rulten S, Tetreault M, Komulainen E, Ju L . XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature. 2016; 541(7635):87-91. PMC: 5218588. DOI: 10.1038/nature20790. View

19.

Komulainen E, Badman J, Rey S, Rulten S, Ju L, Fennell K . Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures. EMBO Rep. 2021; 22(5):e51851. PMC: 8097344. DOI: 10.15252/embr.202051851. View

20.

Zhou W, Doetsch P . Effects of abasic sites and DNA single-strand breaks on prokaryotic RNA polymerases. Proc Natl Acad Sci U S A. 1993; 90(14):6601-5. PMC: 46980. DOI: 10.1073/pnas.90.14.6601. View