Covalent DNA–protein crosslinks (DPCs, also known as protein adducts) of topoisomerases and other proteins with DNA are highly toxic DNA lesions. Of note, chemical agents that induce DPCs include widely used classes of chemotherapeutics. Their bulkiness blocks virtually every chromatin-based process and makes them intractable for repair by canonical repair pathways. Distinct DPC repair pathways employ unique points of attack and are crucial for the maintenance of genome stability. Tyrosyl-DNA phosphodiesterases (TDPs) directly hydrolyse the covalent linkage between protein and DNA. The MRE11–RAD50–NBS1 (MRN) nuclease complex targets the DNA component of DPCs, excising the fragment affected by the lesion, whereas proteases of the spartan (SPRTN)/weak suppressor of SMT3 protein 1 (Wss1) family target the protein component. Loss of these pathways renders cells sensitive to DPC-inducing chemotherapeutics, and DPC repair pathways are thus attractive targets for combination cancer therapy.

中文翻译：

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DNA-蛋白质交联修复机制

拓扑异构酶和其他具有DNA的蛋白质的共价DNA-蛋白质交联（DPC，也称为蛋白质加合物）是高毒性的DNA损伤。值得注意的是，诱导DPC的化学试剂包括广泛使用的化学治疗方法。它们的庞大性实际上阻止了每个基于染色质的过程，并使其难以通过规范的修复途径进行修复。不同的DPC修复途径采用独特的攻击点，对于维持基因组稳定性至关重要。酪氨酰-DNA磷酸二酯酶（TDP）直接水解蛋白质和DNA之间的共价键。MRE11–RAD50–NBS1（MRN）核酸酶复合物靶向DPC的DNA组分，切除受损伤影响的片段，而SMT3蛋白1（Wss1）家族的斯巴达（SPRTN）/弱抑制剂的蛋白酶靶向该蛋白组分。