Proteins that act on DNA, or are in close proximity to it, can become inadvertently crosslinked to DNA and form highly toxic lesions, known as DNA-protein crosslinks (DPCs). DPCs are generated by different chemotherapeutics, environmental or endogenous sources of crosslinking agents, or by lesions on DNA that stall the catalytic cycle of certain DNA processing enzymes. These bulky adducts impair processes on DNA such as DNA replication or transcription, and therefore pose a serious threat to genome integrity. The large diversity of DPCs suggests that there is more than one canonical mechanism to repair them. Indeed, many different enzymes have been shown to act on DPCs by either processing the protein, the DNA or the crosslink itself. In addition, the cell cycle stage or cell type are likely to dictate pathway choice. In recent years, a detailed understanding of DPC repair during S phase has started to emerge. Here, we review the current knowledge on the mechanisms of replication-coupled DPC repair, and describe and also speculate on possible pathways that remove DPCs outside of S phase. Moreover, we highlight a recent paradigm shifting finding that indicates that DPCs are not always detrimental, but can also play a protective role, preserving the genome from more deleterious forms of DNA damage.

作用于DNA或与其密切相关的蛋白质可能会无意间与DNA交联并形成剧毒的损伤，称为DNA-蛋白质交联（DPC）。DPC是由不同的化学治疗剂，环境或内源性交联剂或DNA上的破坏某些DNA处理酶催化周期的损伤产生的。这些庞大的加合物损害了DNA的过程，例如DNA复制或转录，因此对基因组完整性构成了严重威胁。DPC的多样性表明，有多种规范的机制可以修复它们。实际上，已经显示出许多不同的酶通过加工蛋白质，DNA或交联本身而作用于DPC。另外，细胞周期阶段或细胞类型可能决定途径的选择。最近几年，对S阶段DPC维修的详细了解开始浮出水面。在这里，我们回顾了有关复制耦合DPC修复机制的当前知识，并描述并推测了去除S期以外的DPC的可能途径。此外，我们重点介绍了最近的范式转换发现，该发现表明DPC并不总是有害的，但也可以起到保护作用，可以保护基因组免受DNA损害的更有害形式的伤害。