Zhang Huimin, Xiong Yun, Chen Junjie
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX USA.
Cell Biosci. 2020 Jan 7;10:3. doi: 10.1186/s13578-019-0366-z. eCollection 2020.
When a protein is covalently and irreversibly bound to DNA (i.e., a DNA-protein cross-link [DPC]), it may obstruct any DNA-based transaction, such as transcription and replication. DPC formation is very common in cells, as it can arise from endogenous factors, such as aldehyde produced during cell metabolism, or exogenous sources like ionizing radiation, ultraviolet light, and chemotherapeutic agents. DPCs are composed of DNA, protein, and their cross-linked bonds, each of which can be targeted by different repair pathways. Many studies have demonstrated that nucleotide excision repair and homologous recombination can act on DNA molecules and execute nuclease-dependent DPC repair. Enzymes that have evolved to deal specifically with DPC, such as tyrosyl-DNA phosphodiesterases 1 and 2, can directly reverse cross-linked bonds and release DPC from DNA. The newly identified proteolysis pathway, which employs the proteases Wss1 and SprT-like domain at the N-terminus (SPRTN), can directly hydrolyze the proteins in DPCs, thus offering a new venue for DPC repair in cells. A deep understanding of the mechanisms of each pathway and the interplay among them may provide new guidance for targeting DPC repair as a therapeutic strategy for cancer. Here, we summarize the progress in DPC repair field and describe how cells may employ these different repair pathways for efficient repair of DPCs.
当一种蛋白质与DNA发生共价且不可逆的结合（即DNA - 蛋白质交联[DPC]）时，它可能会阻碍任何基于DNA的活动，如转录和复制。DPC的形成在细胞中非常普遍，因为它可能源于内源性因素，如细胞代谢过程中产生的醛，或外源性因素，如电离辐射、紫外线和化疗药物。DPC由DNA、蛋白质及其交联键组成，每一种都可以被不同的修复途径靶向作用。许多研究表明，核苷酸切除修复和同源重组可以作用于DNA分子并执行依赖核酸酶的DPC修复。已经进化出专门处理DPC的酶，如酪氨酰 - DNA磷酸二酯酶1和2，可以直接逆转交联键并从DNA中释放DPC。新发现的蛋白水解途径，它利用蛋白酶Wss1和N端具有SprT样结构域（SPRTN），可以直接水解DPC中的蛋白质，从而为细胞中DPC的修复提供了一种新途径。深入了解每种途径的机制以及它们之间的相互作用，可能为将DPC修复作为癌症治疗策略提供新的指导。在此，我们总结了DPC修复领域的进展，并描述了细胞如何利用这些不同的修复途径来有效修复DPC。
