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.