Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2022 Jul 5

PMID 35782873

Authors

Megan Perry

Gargi Ghosal

Affiliations

Soon will be listed here.

Abstract

DNA-protein crosslinks (DPCs) are deleterious DNA lesions that occur when proteins are covalently crosslinked to the DNA by the action of variety of agents like reactive oxygen species, aldehydes and metabolites, radiation, and chemotherapeutic drugs. Unrepaired DPCs are blockades to all DNA metabolic processes. Specifically, during DNA replication, replication forks stall at DPCs and are vulnerable to fork collapse, causing DNA breakage leading to genome instability and cancer. Replication-coupled DPC repair involves DPC degradation by proteases such as SPRTN or the proteasome and the subsequent removal of DNA-peptide adducts by nucleases and canonical DNA repair pathways. SPRTN is a DNA-dependent metalloprotease that cleaves DPC substrates in a sequence-independent manner and is also required for translesion DNA synthesis following DPC degradation. Biallelic mutations in SPRTN cause Ruijs-Aalfs (RJALS) syndrome, characterized by hepatocellular carcinoma and segmental progeria, indicating the critical role for SPRTN and DPC repair pathway in genome maintenance. In this review, we will discuss the mechanism of replication-coupled DPC repair, regulation of SPRTN function and its implications in human disease and cancer.

Citing Articles

Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers.

Goncalves T, Cunniffe S, Ma T, Mattis N, Rose A, Kent T Nucleic Acids Res. 2025; 53(4).

PMID: 39921567 PMC: 11806356. DOI: 10.1093/nar/gkaf061.

Purification and Identification of the Nematicidal Activity of S1 Family Trypsin-Like Serine Protease (PRA1) from T6 Through Prokaryotic Expression and Biological Function Assays.

Ma N, Lv H, Boamah S, Zhang S, Xu B Genes (Basel). 2024; 15(11).

PMID: 39596637 PMC: 11593352. DOI: 10.3390/genes15111437.

Acute exposure to dihydroxyacetone promotes genotoxicity and chromosomal instability in lung, cardiac, and liver cell models.

Hernandez A, Hedlich-Dwyer J, Hussain S, Levi H, Sonavane M, Suzuki T Toxicol Sci. 2024; 201(1):85-102.

PMID: 38867704 PMC: 11347775. DOI: 10.1093/toxsci/kfae075.

Recurrent Duplication and Diversification of a Vital DNA Repair Gene Family Across Drosophila.

Brand C, Oliver G, Farkas I, Buszczak M, Levine M Mol Biol Evol. 2024; 41(6).

PMID: 38865490 PMC: 11210505. DOI: 10.1093/molbev/msae113.

Enzymatic Processing of DNA-Protein Crosslinks.

Essawy M, Campbell C Genes (Basel). 2024; 15(1).

PMID: 38254974 PMC: 10815813. DOI: 10.3390/genes15010085.

References

Juttermann R, Li E, Jaenisch R . Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci U S A. 1994; 91(25):11797-801. PMC: 45322. DOI: 10.1073/pnas.91.25.11797. View

Chvalova K, Brabec V, Kasparkova J . Mechanism of the formation of DNA-protein cross-links by antitumor cisplatin. Nucleic Acids Res. 2007; 35(6):1812-21. PMC: 1874601. DOI: 10.1093/nar/gkm032. View

Reinking H, Kang H, Gotz M, Li H, Kieser A, Zhao S . DNA Structure-Specific Cleavage of DNA-Protein Crosslinks by the SPRTN Protease. Mol Cell. 2020; 80(1):102-113.e6. PMC: 7534798. DOI: 10.1016/j.molcel.2020.08.003. View

Mao Y, Desai S, Ting C, Hwang J, Liu L . 26 S proteasome-mediated degradation of topoisomerase II cleavable complexes. J Biol Chem. 2001; 276(44):40652-8. DOI: 10.1074/jbc.M104009200. View

Prasad R, Horton J, Dai D, Wilson S . Repair pathway for PARP-1 DNA-protein crosslinks. DNA Repair (Amst). 2018; 73:71-77. PMC: 6312470. DOI: 10.1016/j.dnarep.2018.11.004. View

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

Chanet R, Izard C, MOUSTACCHI E . Genetic effects of formaldehyde in yeast. II. Influence of ploidly and of mutations affecting radiosensitivity on its lethal effect. Mutat Res. 1976; 35(1):29-38. DOI: 10.1016/0027-5107(76)90166-4. View

Fielden J, Wiseman K, Torrecilla I, Li S, Hume S, Chiang S . TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nat Commun. 2020; 11(1):1274. PMC: 7062751. DOI: 10.1038/s41467-020-15000-w. View

Swenberg J, Lu K, Moeller B, Gao L, Upton P, Nakamura J . Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol Sci. 2010; 120 Suppl 1:S130-45. PMC: 3043087. DOI: 10.1093/toxsci/kfq371. View

10.

Wei X, Peng Y, Bryan C, Yang K . Mechanisms of DNA-protein cross-link formation and repair. Biochim Biophys Acta Proteins Proteom. 2021; 1869(8):140669. DOI: 10.1016/j.bbapap.2021.140669. View

11.

Hoeller D, Crosetto N, Blagoev B, Raiborg C, Tikkanen R, Wagner S . Regulation of ubiquitin-binding proteins by monoubiquitination. Nat Cell Biol. 2006; 8(2):163-9. DOI: 10.1038/ncb1354. View

12.

Pohlhaus J, Kreuzer K . Norfloxacin-induced DNA gyrase cleavage complexes block Escherichia coli replication forks, causing double-stranded breaks in vivo. Mol Microbiol. 2005; 56(6):1416-29. PMC: 1201555. DOI: 10.1111/j.1365-2958.2005.04638.x. View

13.

Deshpande R, Lee J, Arora S, Paull T . Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts. Mol Cell. 2016; 64(3):593-606. DOI: 10.1016/j.molcel.2016.10.010. View

14.

Juhasz S, Balogh D, Hajdu I, Burkovics P, Villamil M, Zhuang Z . Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance. Nucleic Acids Res. 2012; 40(21):10795-808. PMC: 3510514. DOI: 10.1093/nar/gks850. View

15.

de Graaf B, Clore A, McCullough A . Cellular pathways for DNA repair and damage tolerance of formaldehyde-induced DNA-protein crosslinks. DNA Repair (Amst). 2009; 8(10):1207-14. PMC: 2748227. DOI: 10.1016/j.dnarep.2009.06.007. View

16.

Larsen N, Gao A, Sparks J, Gallina I, Wu R, Mann M . Replication-Coupled DNA-Protein Crosslink Repair by SPRTN and the Proteasome in Xenopus Egg Extracts. Mol Cell. 2019; 73(3):574-588.e7. PMC: 6375733. DOI: 10.1016/j.molcel.2018.11.024. View

17.

Vaz B, Popovic M, Newman J, Fielden J, Aitkenhead H, Halder S . Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Mol Cell. 2016; 64(4):704-719. PMC: 5128727. DOI: 10.1016/j.molcel.2016.09.032. View

18.

Stingele J, Habermann B, Jentsch S . DNA-protein crosslink repair: proteases as DNA repair enzymes. Trends Biochem Sci. 2014; 40(2):67-71. DOI: 10.1016/j.tibs.2014.10.012. View

19.

Yeo J, Wickramaratne S, Khatwani S, Wang Y, Vervacke J, Distefano M . Synthesis of site-specific DNA-protein conjugates and their effects on DNA replication. ACS Chem Biol. 2014; 9(8):1860-8. PMC: 4136702. DOI: 10.1021/cb5001795. View

20.

Woodworth D, Kreuzer K . Bacteriophage T4 mutants hypersensitive to an antitumor agent that induces topoisomerase-DNA cleavage complexes. Genetics. 1996; 143(3):1081-90. PMC: 1207380. DOI: 10.1093/genetics/143.3.1081. View