Enzymatic repair of covalently crosslinked DNA

The reaction of bifunctional reagents with the genome results in potentially lethal DNA interstrand crosslinks (ICLs). Failure to repair DNA ICLs leads to cell death, which is exploited therapeutically (cis-platin), but can in turn lead to a number of disease states. Nevertheless, the details of ICL repair remain elusive. A number of DNA repair pathways have been implicated in the repair of ICLs including both nucleotide and base excision alongside the fanconia anaemia pathway. A large obstacle to the study of ICLs is the inability to generate in vitro many of the crosslinks that actually occur in vivo. Thus most studies have used synthetic crosslinked DNA where a surrogate crosslink is employed that is chemically altered (often drastically) from its actual in vivo form. Notably several of these synthetic ICLs actually join different nucleobase functional groups that are in different grooves of the DNA compared to the natural ICL. This has, on occasion, led to puzzling proposals where enzymes that would be predicted to be inhibited by certain ICLs are suggested to process them.