DNA Interstrand Crosslink Repair

Abstract

Crosslinking agents such as psoralens, nitrogen mustards or cisplatin are bifunctionally acting chemicals that generate some adducts as covalent linkages between complementary deoxyribonucleic acid strands. Since many agents are of importance in genetic toxicology and cancer therapy, repair of interstrand crosslinks has been studied extensively in bacteria and in lower and higher eukaryotes. The main repair pathway in Escherichia coli involves the sequential action of nucleotide excision repair and recombinational repair. In eukaryotes, nucleotide excision repair, translesion synthesis and homologous recombination all play important roles in crosslink repair. Instances where crosslink unhooking is performed by a glycosylase have also been observed. The relative pathway contribution depends on cell cycle position and agent used. Analysis of mammalian crosslink response proteins that are also involved in the hereditary syndrome Fanconi anaemia resulted in a model of crosslink repair within the context of converging replicons arrested by an interstrand crosslink.

Key Concepts

  • Certain chemicals with two or more correctly spaced reactive groups can covalently link opposing DNA strands.
  • Several repair or tolerance pathways such as nucleotide excision repair, homologous recombination, translesion synthesis and even DNA glycosylases can work together to overcome such complex damage.
  • Cell cycle stage may determine the choice of repair pathway or pathway combinations.
  • A heritable human cancer‐prone syndrome with diverse phenotypes (Fanconi anaemia) has been linked to defects in crosslink repair.
  • By integrating in vitro studies and the analysis of Fanconi proteins, a model for mammalian cells places replication‐coupled crosslink repair at the convergence point of stalled replication forks.
  • This model includes a sequence of unhooking of the interstrand crosslink by structure‐specific endonucleases, filling of the created single‐stranded gap by translesion synthesis and repair of the double‐strand break in the sister chromatid by one of several pathways, including homologous recombination.

Keywords: DNA repair; crosslinks; excision; bifunctional alkylation; recombination; translesion synthesis; Fanconi anaemia

Figure 1. Examples of crosslinking agents and their primary interstrand crosslink adduct. (a) Nitrogen mustard, (b) mitomycin C, (c) cisplatin, (d) methoxypsoralen, (e) nitrosourea, (f) diepoxybutane, (g) aldehyde and (h) nitric oxide. From Lopez‐Martinez D, Liang CC and Cohn MA (2016) Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway. Cellular and Molecular Life Sciences 73: 3097–3114, Licensed under CC BY.
Figure 2. Repair of an ICL in E. coli. (a) In the main pathway, first, a single‐stranded DNA fragment is removed by NER by cutting 3′ and 5′ of the crosslink. It stays attached to the complementary strand through the crosslink. A gap is formed by the exonuclease activity of Pol I. The single‐stranded gap is filled by RecA‐dependent strand invasion as the initial step of HR, and a second round of NER releases a partially double‐stranded fragment containing the crosslink. (b) The minor pathway found in stationary cells also starts with crosslink excision. Then, however, DNA polymerase II (β) performs translesion synthesis and a second round of NER releases the same product as in (a). From Dronkert ML and Kanaar R Repair of DNA interstrand crosslinks. Mutation Research 486: 217–247 © Elsevier.
Figure 3. Model for replication‐coupled DNA crosslink repair, based on studies of a cell‐free system. (a) Plasmid substrate, containing a single ICL in a defined position.From Räschle M, Knipscheer P, Enoiu M et al. (2008) Mechanism of replication‐coupled DNA interstrand crosslink repair. Cell 134: 969–980. © Elsevier. (b) Electron microscopy analysis of replication of this substrate, following cell extract addition.Reproduced with permission from Räschle et al. . © Cell Press and Elsevier. (c) Scheme for crosslink processing. The assumption of converging and stalled replication forks may lead to simultaneous double‐strand breakage and unhooking of the crosslink. Compare to Figure , a similar scheme that includes candidate proteins. From Räschle M, Knipscheer P, Enoiu M et al. (2008) Mechanism of replication‐coupled DNA interstrand crosslink repair. Cell 134: 969–980. © Elsevier.
Figure 4. Model for replication‐coupled DNA crosslink repair, incorporating studies on FA proteins. (a,b) Removal of the replicative CMG helicase following its ubiquitination by TRAIP sets the stage for ICL recognition by the FANCM‐containing anchoring complex. Following stabilisation of the stalled replication fork, the FA core complex joins and carries out the monoubiquitination of FANCI/FANCD2 heterodimer (ID2). (c) Through binding of the UBZ4 domain‐containing scaffold protein, SLX4 brings in structure‐specific endonucleases (ERCC1–XPF is shown) that may cut in sequential or redundant fashion to unhook the crosslink. This may also include FAN1. (d) Next, TLS is carried out by REV1/Polζ (mainly). The unhooked crosslink may later undergo complete removal by NER. (e) The double‐strand break in the sister chromatid will undergo end resection and repair by HR, microhomology‐mediated or nonhomologous end joining (the details of these processes are not subject of this review). From Liu W, Palovcak A, Li F, Zafar A, Yuan F and Zhang Y (2020) Fanconi anemia pathway as a prospective target for cancer intervention. Cell & Bioscience 10: 39. Licensed under CC BY 4.0.
close

References

Andreassen PR, D'Andrea AD and Taniguchi T (2004) ATR couples FANCD2 monoubiquitination to the DNA‐damage response. Genes and Development 18: 1958–1963.

Berardini M, Foster PL and Loechler EL (1999) DNA polymerase II (polB) is involved in a new DNA repair pathway for DNA interstrand cross‐links in E. coli. Journal of Bacteriology 181: 2878–2882.

Bossuet‐Greif N, Vignard J, Taieb F, et al. (2018) The colibactin genotoxin generates DNA interstrand cross‐links in infected cells. mBio 9: e02393‐17.

Bradley NP, Washburn LA, Christov PP, Watanabe CMH and Eichman BF (2020) Escherichia coli YcaQ is a DNA glycosylase that unhooks DNA interstrand crosslinks. Nucleic Acids Research 48: 7005–7017.

Budzowska M, Graham TG, Sobeck A, Waga S and Walter JC (2015) Regulation of the Rev1‐pol zeta complex during bypass of a DNA interstrand cross‐link. EMBO Journal 34: 1971–1985.

Ceccaldi R, Sarangi P and D'Andrea AD (2016) The Fanconi anaemia pathway: new players and new functions. Nature Reviews in Molecular Cell Biology 17: 337–349.

Chen YH, Jones MJ, Yin Y, et al. (2015) ATR‐mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Molecular Cell 58: 323–338.

Deans AJ and West SC (2011) DNA interstrand crosslink repair and cancer. Nature Reviews Cancer 11: 467–480.

Dronkert ML and Kanaar R (2001) Repair of DNA interstrand crosslinks. Mutation Research 486: 217–247.

Friedberg EC, Walker GC, Siede W, et al. (2006) DNA Repair and Mutagenesis, 2nd edn. American Society of Microbiology Press: Washington, DC.

Guervilly JH and Gaillard PH (2018) SLX4: multitasking to maintain genome stability. Critical Reviews in Biochemistry and Molecular Biology 53: 475–514.

Hodskinson MR, Bolner A, Sato K, et al. (2020) Alcohol‐derived DNA crosslinks are repaired by two distinct mechanisms. Nature 579: 603–608.

van Houten B, Gamper H, Holbrook SR, Hearst JE and Sancar A (1986) Action mechanism of ABC excision nuclease on a DNA substrate containing a psoralen crosslink at a defined position. Proceedings of the National Academy of Sciences of the United States of America 83: 8077–8081.

Hwang IG, Ahn MJ, Park BB, et al. (2008) ERCC1 expression as a prognostic marker in N2(+) nonsmall‐cell lung cancer patients treated with platinum‐based neoadjuvant concurrent chemoradiotherapy. Cancer 113: 1379–1386.

Iyama T, Lee SY, Berquist BR, et al. (2015) CSB interacts with SNM1A and promotes DNA interstrand crosslink processing. Nucleic Acids Research 43: 247–258.

Jachymczyk WJ, von Borstel RC, Mowat MR and Hastings PJ (1981) Repair of interstrand cross‐links in DNA of Saccharomyces cerevisiae requires two systems for DNA repair: the RAD3 system and the RAD51 system. Molecular and General Genetics 182: 196–205.

Kim H and D'Andrea AD (2012) Regulation of DNA cross‐link repair by the Fanconi anemia/BRCA pathway. Genes & Development 26: 1393–1408.

Kim H, Yang K, Dejsuphong D and D'Andrea AD (2012) Regulation of Rev1 by the Fanconi anemia core complex. Nature Structural and Molecular Biology 19: 164–170.

Klein Douwel D, Boonen RA, Long DT, et al. (2014) XPF‐ERCC1 acts in unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Molecular Cell 54: 460–471.

Knipscheer P, Raschle M, Smogorzewska A, et al. (2009) The Fanconi anemia pathway promotes replication‐dependent DNA interstrand cross‐link repair. Science 326: 1698–1701.

Kottemann MC and Smogorzewska A (2013) Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature 493: 356–363.

Lachaud C, Moreno A, Marchesi F, et al. (2016) Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. Science 351: 846–849.

Langevin F, Crossan GP, Rosado IV, Arends MJ and Patel KJ (2011) Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475: 53–58.

Lehoczky P, McHugh PJ and Chovanec M (2007) DNA interstrand cross‐link repair in Saccharomyces cerevisiae. FEMS Microbiological Reviews 31: 109–133.

Li X, Hejna J and Moses R (2005) The yeast Snm1 protein is a DNA 5′‐exonuclease. DNA Repair 4: 163–170.

Li N, Wang J, Wallace SS, et al. (2020) Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair. Nucleic Acids Research 48: 3014–3028.

Liu W, Palovcak A, Li F, et al. (2020) Fanconi anemia pathway as a prospective target for cancer intervention. Cell & Bioscience 10: 39.

Long DT, Joukov V, Budzowska M and Walter JC (2014) BRCA1 promotes unloading of the CMG helicase from a stalled DNA replication fork. Molecular Cell 56: 174–185.

Lopez‐Martinez D, Liang CC and Cohn MA (2016) Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway. Cellular and Molecular Life Sciences 73: 3097–3114.

Magaña‐Schwencke N, Henriques JAP, Chanet R and Moustacchi E (1982) The fate of 8‐methoxypsoralen photoinduced cross‐links in nuclear and mitochondrial yeast DNA: comparison of wild type and repair deficient strain. Proceedings of the National Academy of Sciences of the United States of America 79: 1722–1726.

Mamenta EL, Poma EE, Kaufmann WK, et al. (1994) Enhanced replicative bypass of platinum‐DNA adducts in cisplatin‐resistant human ovarian carcinoma cell lines. Cancer Research 54: 3500–3505.

Moldovan GL, Madhavan MV, Mirchandani KD, et al. (2010) DNA polymerase POLN participates in cross‐link repair and homologous recombination. Molecular and Cellular Biology 30: 1088–1096.

Mukherjee A and Vasquez KM (2016) HMGB1 interacts with XPA to facilitate the processing of DNA interstrand crosslinks in human cells. Nucleic Acids Research 44: 1151–1160.

Niedernhofer LJ, Odijk H, Budzowska M, et al. (2004) The structure‐specific endonuclease Ercc1‐Xpf is required to resolve DNA interstrand cross‐link‐induced double‐strand breaks. Molecular and Cellular Biology 24: 5776–5787.

Niraj J, Färkkilä A and D'Andrea AD (2019) The Fanconi anemia pathway in cancer. Annual Review of Cancer Biology 3: 457–478.

Oestergaard VH, Langevin F, Kuiken HJ, et al. (2007) Deubiquitination of FANCD2 is required for DNA crosslink repair. Molecular Cell 28: 798–809.

Pichierri P and Rosselli F (2004) The DNA crosslink‐induced S‐phase checkpoint depends on ATR‐CHK1 and ATR‐NBS1‐FANCD2 pathways. EMBO Journal 23: 1178–1187.

Price NE, Johnson KM, Wang J, et al. (2014) Interstrand DNA‐DNA cross‐link formation between adenine residues and abasic sites in duplex DNA. Journal of the American Chemical Society 136: 3483–3490.

Räschle M, Knipscheer P, Enoiu M, et al. (2008) Mechanism of replication‐coupled DNA interstrand crosslink repair. Cell 134: 969–980.

Roy U and Schärer OD (2016) Involvement of translesion synthesis DNA polymerases in DNA interstrand crosslink repair. DNA Repair 44: 33–41.

Ruhland A, Kircher M, Wilborn F and Brendel M (1981) A yeast mutant specifically sensitive to bifunctional alkylation. Mutation Research 91: 457–462.

Semlow DR, Zhang J, Budzowska M, Drohat AC and Walter JC (2016) Replication‐dependent unhooking of DNA interstrand cross‐links by the NEIL3 glycosylase. Cell 167: 498–511.e414.

Sladek FM, Munn MM, Rupp WD and Howard‐Flanders P (1989) In vitro repair of psoralen‐DNA cross‐links by RecA, UvrABC, and the 5′‐exonuclease of DNA polymerase I. Journal of Biological Chemistry 264: 6755–6765.

Stingele J, Bellelli R and Boulton SJ (2017) Mechanisms of DNA‐protein crosslink repair. Nature Reviews Molecular Cell Biology 18: 563–573.

Takata M, Sasaki MS, Tachiri S, et al. (2001) Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Molecular and Cellular Biology 21: 2858–2866.

Vos J‐MH and Hanawalt PC (1987) Processing of psoralen adducts in an active human gene: repair and replication of DNA containing monoadducts and interstrand cross‐links. Cell 50: 789–799.

Williams HL, Gottesman ME and Gautier J (2013) The differences between ICL repair during and outside of S phase. Trends in Biochemical Sciences 38: 386–393.

Wu F, Lin X, Okuda T and Howell SB (2004) DNA polymerase zeta regulates cisplatin cytotoxicity, mutagenicity, and the rate of development of cisplatin resistance. Cancer Research 64: 8029–8035.

Wu RA, Semlow DR, Kamimae‐Lanning AN, et al. (2019) TRAIP is a master regulator of DNA interstrand crosslink repair. Nature 567: 267–272.

Zheng H, Wang X, Warren AJ, et al. (2003) Nucleotide excision repair‐ and polymerase eta‐mediated error‐prone removal of mitomycin C interstrand cross‐links. Molecular and Cellular Biology 23: 754–761.

Further Reading

Brendel M and Ruhland A (1984) Relationships between functionality and genetic toxicology of selected DNA damaging agents. Mutation Research 133: 51–85.

Chatterjee B and Siede W (2013) Replicating damaged DNA in eukaryotes. Cold Spring Harbor Perspectives Biology 5: a019836.

Cortez D (2019) Replication‐coupled DNA repair. Molecular Cell 74: 866–876.

Lange SS, Takata K and Wood RD (2011) DNA polymerases and cancer. Nature Reviews Cancer 11: 96–110.

Roy U, Mukherjee S, Sharma A, Frank EG and Schärer OD (2016) The structure and duplex context of DNA interstrand crosslinks affects the activity of DNA polymerase eta. Nucleic Acids Research 44: 7281–7291.

Rycenga HB and Long DT (2018) The evolving role of DNA inter‐strand crosslinks in chemotherapy. Current Opinion Pharmacology 41: 20–26.

Sakai W and Sugasawa K (2019) Importance of finding the bona fide target of the Fanconi anemia pathway. Genes and Environment 41: 6.

Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22: 7265–7279.

Song PS and Tapley KJ (1979) Photochemistry and photobiology of psoralens. Photochemistry and Photobiology 29: 1177–1197.

Wood RD (2010) Mammalian nucleotide excision repair proteins and interstrand crosslink repair. Environmental and Molecular Mutagenesis 51: 520–526.

Wu Q and Vasquez KM (2008) Human MLH1 protein participates in genomic damage checkpoint signaling in response to DNA interstrand crosslinks, while MSH2 functions in DNA repair. PLoS Genet 4: e1000189.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Siede, Wolfram(Dec 2020) DNA Interstrand Crosslink Repair. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029226]