Enzymatic repair of covalently crosslinked DNA

双功能试剂与基因组的反应会导致潜在的致命性DNA链间交联(ICL)。未能修复DNA ICL会导致细胞死亡，这可用于治疗(顺铂)，但反过来可能导致许多疾病状态。然而，ICL修复的细节仍然难以捉摸。许多DNA修复途径与ICL的修复有关，包括核苷酸和碱基切除，以及扇形贫血途径。ICL研究的一大障碍是无法在体外产生许多在体内实际发生的交联物。因此，大多数研究都使用了合成的交联型DNA，其中使用了一种替代交联剂，这种交联剂与其在体内的实际形式相比发生了化学上的改变(通常是剧烈的)。值得注意的是，这些合成的ICL中的几个实际上加入了与天然ICL相比位于DNA不同沟槽中的不同的核苷酸碱基功能基团。这有时会导致令人费解的建议，建议使用某些ICL预测会抑制的酶来处理它们。

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.