DNA inter-strand crosslinks (ICLs) are dangerous lesions that can be caused by a variety of endogenous and exogenous bifunctional compounds. Because covalently linking both strands of the double helix locally disrupts DNA replication and transcription, failure to remove even a single ICL can be fatal to the cell. Thus, multiple ICL repair pathways have evolved, with the best studied being the canonical Fanconi anemia (FA) pathway. However, recent research demonstrates that different types of ICLs (e.g., backbone distorting vs. non-distorting) can be discriminated by the cell, which then mounts a specific repair response using the FA pathway or one of a variety of FA-independent ICL repair pathways. This review focuses on the latter, covering current work on the transcription-coupled, base excision, acetaldehyde-induced, and SNM1A/RecQ4 ICL repair pathways and highlighting unanswered questions in the field. Answering these questions will provide mechanistic insight into the various pathways of ICL repair and enable ICL-inducing agents to be more effectively used as chemotherapeutics.

DNA链间交联（ICL）是危险的病变，可能由多种内源性和外源性双功能化合物引起。由于共价连接双螺旋的两条链会局部破坏DNA复制和转录，因此即使去除单个ICL也会失败，对细胞致命。因此，已经发展了多种ICL修复途径，其中研究得最好的是典型的范可尼贫血（FA）途径。然而，最近的研究表明，不同类型的ICL（例如，主干失真与不可区分的细胞），然后使用FA途径或多种独立于FA的ICL修复途径之一启动特定的修复反应。这篇综述的重点是后者，涵盖了目前有关转录偶联，碱基切除，乙醛诱导的和SNM1A / RecQ4 ICL修复途径的工作，并重点介绍了该领域中尚未解决的问题。回答这些问题将提供对ICL修复各种途径的机械洞察力，并使ICL诱导剂更有效地用作化学治疗药。