Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States; Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, United States.
Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States.
Biochim Biophys Acta Proteins Proteom. 2021 Aug;1869(8):140669. doi: 10.1016/j.bbapap.2021.140669. Epub 2021 May 3.
Covalent binding of DNA to proteins produces DNA-protein cross-links (DPCs). DPCs are formed as intermediates of enzymatic processes, generated from the reactions of protein nucleophiles with DNA electrophiles, and produced by endogenous and exogenous cross-linking agents. DPCs are heterogeneous due to the variations of DNA conjugation sites, flanking DNA structures, protein sizes, and cross-link bonds. Unrepaired DPCs are toxic because their bulky sizes physically block DNA replication and transcription, resulting in impaired genomic integrity. Compared to other types of DNA lesions, DPC repair is less understood. Emerging evidence suggests a general repair model that DPCs are proteolyzed by the proteasome and/or DPC proteases, followed by the peptide removal through canonical repair pathways. Herein, we first describe the recently discovered DPCs. We then review the mechanisms of DPC proteolysis with the focus on recently identified DPC proteases. Finally, distinct pathways that bypass or remove the cross-linked peptides following proteolysis are discussed.
DNA 与蛋白质的共价结合会产生 DNA-蛋白质交联物（DPCs）。DPCs 是酶促过程的中间产物，由蛋白质亲核试剂与 DNA 亲电试剂的反应生成，并由内源性和外源性交联剂产生。由于 DNA 连接位点、侧翼 DNA 结构、蛋白质大小和交联键的变化，DPCs 具有异质性。未修复的 DPCs 是有毒的，因为它们的体积庞大会物理性地阻止 DNA 复制和转录，从而导致基因组完整性受损。与其他类型的 DNA 损伤相比，DPC 修复的了解较少。新出现的证据表明了一种普遍的修复模型，即 DPC 被蛋白酶体和/或 DPC 蛋白酶切割，然后通过经典的修复途径去除肽段。在此，我们首先描述了最近发现的 DPCs。然后，我们回顾了 DPC 切割的机制，重点介绍了最近发现的 DPC 蛋白酶。最后，讨论了蛋白酶切割后绕过或去除交联肽段的不同途径。
