Covalent DNA-protein crosslinks (DPCs) are highly toxic DNA adducts, which interfere with faithful DNA replication. The proteases Wss1 and SPRTN degrade DPCs and have emerged as crucially important DNA repair enzymes. Their protective role has been described in various model systems ranging from yeasts, plants, worms and flies to mice and humans. Loss of DPC proteases results in genome instability, cellular arrest, premature ageing and cancer predisposition. Here we discuss recent insights into the function and molecular mechanism of these enzymes. Furthermore, we present an in-depth phylogenetic analysis of the Wss1/SPRTN protease continuum. Remarkably flexible domain architectures and constantly changing protein-protein interaction motifs indicate ongoing evolutionary dynamics. Finally, we discuss recent data, which suggest that further partially-overlapping proteolytic systems targeting DPCs exist in eukaryotes. These new developments raise interesting questions regarding the division of labour between different DPC proteases and the mechanisms and principles of repair pathway choice.

中文翻译：

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DNA-蛋白质交联蛋白酶 Wss1 和 SPRTN 的功能和进化。

共价 DNA-蛋白质交联 (DPC) 是剧毒的 DNA 加合物，会干扰 DNA 的忠实复制。蛋白酶 Wss1 和 SPRTN 可降解 DPC，并已成为至关重要的 DNA 修复酶。它们的保护作用已在从酵母、植物、蠕虫和苍蝇到小鼠​​和人类的各种模型系统中得到描述。DPC 蛋白酶的缺失导致基因组不稳定、细胞停滞、过早衰老和癌症易感性。在这里，我们讨论了对这些酶的功能和分子机制的最新见解。此外，我们对 Wss1/SPRTN 蛋白酶连续体进行了深入的系统发育分析。非常灵活的域结构和不断变化的蛋白质-蛋白质相互作用基序表明正在进行的进化动力学。最后，我们讨论最近的数据，这表明在真核生物中存在针对 DPC 的进一步部分重叠的蛋白水解系统。这些新的发展提出了关于不同 DPC 蛋白酶之间的分工以及修复途径选择的机制和原则的有趣问题。