Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
Sci China Life Sci. 2017 Oct;60(10):1065-1076. doi: 10.1007/s11427-017-9183-4. Epub 2017 Oct 30.
DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks (DPCs)-the covalent linkage of proteins with a DNA strand-are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation. Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.
DNA 经常暴露于各种遗传毒性物质中，从而产生多种形式的 DNA 损伤。DNA-蛋白质交联（DPC）——蛋白质与 DNA 链的共价连接——是最具危害性和研究最少的 DNA 损伤形式之一，它对转录和复制构成空间位阻。如果这些损伤得不到适当的修复，就可能导致突变、基因组不稳定性和细胞死亡。DPC 可由内源性因素或环境致癌物和化疗药物诱导产生。内源性 DPC 通常通过与醛类的反应以及通过将各种酶中间体捕获到 DNA 上而产生。DPC 中蛋白质部分的蛋白水解切割是去除损伤的一种通用策略。这可以通过 DPC 特异性蛋白酶和/或蛋白酶体介导的降解来实现。核苷酸切除修复和同源重组都参与了 DPC 的修复，其各自的作用可能取决于加合物的性质和大小。范可尼贫血途径也可能在处理 DPC 修复中间体中发挥作用。在这篇综述中，我们讨论了这些损伤是如何形成的，以及去除它们的策略和机制，以及与 DPC 修复缺陷相关的疾病。
