DNA Interstrand Crosslink Repair

Abstract

Crosslinking agents such as psoralens, nitrogen mustards or cisplatin are bifunctionally acting chemicals that generate a fraction of their adducts as covalent linkages between complementary deoxyribonucleic acid strands. Since many of these 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 (NER) and recombinational repair. In eukaryotes, several repair pathways play important roles not only in repair including NER, translesion synthesis and recombination, but also mismatch repair. Relative contributions of the various pathways depend on cell cycle position and agent used. Eukaryotic proteins that specifically enhance resistance to crosslinking agents have been identified (FANC family of proteins, SNM1).

Key Concepts:

  • 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, recombination and translesion synthesis can work together to overcome such complex damage.

  • Cell cycle stage may determine the choice of repair pathway combinations.

  • A heritable human syndrome with multiple diverse phenotypes (Fanconi anaemia) has been associated with defects in crosslink repair.

  • By integrating in vitro studies and analysis of Fanconi proteins, current models of replication‚Äźdependent crosslink repair assume the creation of double strand breaks at stalled replication forks that are repaired by homologous recombination.

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

Figure 1.

Examples of ICL structures. (a) Nitrogen mustard, (b) cisplatin and (c) methoxypsoralen. Reproduced with permission from Noll et al. (). © Frontiers in Bioscience.

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 excision releases a partially double‐stranded fragment containing the crosslink. (b) The minor pathway found in stationary cells also starts with crosslink excision. Then, however, polymerase II (β) performs translesion synthesis and a second round of NER releases the same product as in (a). Reproduced with permission from Dronkert and Kanaar (). © Elsevier.

Figure 3.

DNA crosslink processing in higher eukaryotes in the context of replication. It is assumed that replication fork stalling or collapse leads to origination of a double‐strand break by structure‐specific endonucleases. Considerable redundancy of their activities is expected. This appears to be a precondition for incision around the crosslink (‘unhooking’), possibly associated by single‐stranded DNA degradation. Checkpoint proteins that respond to single‐stranded DNA and double strand breaks participate as important signalling factors that also may attract repair proteins. Many known proteins involved are listed but details remain unknown.

Figure 4.

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. (b) Electron microscopy analysis of replication of this substrate, following cell extract addition. (c) Scheme for crosslink processing (see text for details). Note that in contrast to Figure , the assumption of converging and stalled replication forks leads to simultaneous double‐strand breakage and unhooking of the crosslink. See Figure for a similar scheme that includes candidate proteins. Reproduced with permission from Räschle et al. (). © Cell Press and Elsevier.

Figure 5.

Model for replication‐coupled DNA crosslink repair, incorporating studies on Fanconi syndrome proteins. Following stabilisation of the stalled replication fork, the FA core complex results in monoubiquitination of FANCI and FANCD2. Through binding of the UBZ4 domain‐containing protein, SLX4 (= FANCP), ERCC1–XPF, MUS81‐EME1 or UBZ4 containing FAN1 may cut in sequential or redundant fashion to unhook the crosslink. TLS is initiated, followed by HR. FANCD1, J, N, O represent recombination proteins. The unhooked crosslink may undergo complete removal by NER. Reproduced from Kim and D'Andrea (). © Creative Commons.

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Further Reading

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Siede, Wolfram(Aug 2014) DNA Interstrand Crosslink Repair. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000575.pub3]