DNA Interstrand Crosslink Repair

Wolfram Siede, University of North Texas Health Science Center, Fort Worth, Texas, USA

Published online: December 2009

DOI: 10.1002/9780470015902.a0000575.pub2

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 (ICL) has been studied extensively in prokaryotes and in lower and higher eukaryotes. The main repair pathway in E. coli involves the sequential action of nucleotide excision repair and recombinational repair. In eukaryotes, several repair pathways play important roles not only in repair including nucleotide excision repair, translesion synthesis, 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 (SNM1, FANC family of proteins).

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 seemingly deleterious consequence of complex DNA damage (replication fork collapse at a crosslinked site) can be an important integrated part of damage tolerance and repair.
  • A heritable human syndrome with multiple diverse phenotypes (Fanconi anaemia) can be associated with a specific DNA repair deficiency (crosslink repair).

Keywords: DNA repair; crosslinks; excision; alkylation; recombination

Figure 1. Examples of interstrand crosslink structures. (a) Nitrogen mustard, (b) cisplatin and (c) methoxypsoralen. Reproduced with permission from Noll et al. (2004).
Figure 2. Repair of an interstrand crosslink in E. coli. (a) In the main pathway, first a single-stranded DNA fragment is removed by nucleotide excision repair 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 homologous recombination 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 () performs translesion synthesis and a second round of nucleotide excision repair releases the same product as in (a). Reproduced from Dronkert and Kanaar (2001). Reproduced with permission from Elsevier.
Figure 3. DNA crosslink processing in higher eukaryotes in the context of replication. It is assumed that replication fork collapse leads to origination of a double-strand break by structure-specific endonucleases. 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 attract repair proteins. Many known proteins involved are listed; the overall scheme, however, is still largely hypothetical and most details are unknown.
Figure 4. Model for replication-coupled DNA crosslink repair, based on studies of a cell-free system. (a) Plasmid substrate, containing a single interstrand crosslink 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 3, the assumption of converging and stalled replication forks leads to simultaneous double-strand breakage and unhooking of the crosslink. From Räschle et al., 2008, reproduced by permission of Cell Press.
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Related Sub-Topics:

DNA Damage and Repair | Biomolecular Interactions | Nucleic Acids: Structure, Function, Metabolism
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Article Title: DNA Interstrand Crosslink Repair
 
How to Cite close
Siede, Wolfram(Dec 2009) DNA Interstrand Crosslink Repair. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000575.pub2]