Enzymatic repair of covalently crosslinked DNA

共价交联 DNA 的酶促修复

• 批准号: 2594284
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2594284
• 关键词: Enzymatic; repair; 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.

双功能试剂与基因组的反应导致潜在致命的DNA链间交联（ICL）。不能修复DNA ICL导致细胞死亡，这是治疗上利用（顺铂），但反过来又会导致许多疾病状态。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范康尼亚贫血途径。ICL研究的一大障碍是不能在体外产生许多实际上在体内发生的交联。因此，大多数研究使用合成的交联DNA，其中使用从其实际体内形式化学改变（通常急剧地）的替代交联。值得注意的是，与天然ICL相比，这些合成ICL中的几个实际上加入了不同的核碱基官能团，这些官能团位于DNA的不同凹槽中。有时，这导致了令人困惑的建议，其中预测会被某些ICL抑制的酶被建议处理它们。