Repair of DNA-polypeptide crosslinks by human excision nuclease
Repair of DNA-polypeptide crosslinks by human excision nuclease
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DOI：
10.1073/pnas.0600538103
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发表时间：
2006-03-14
影响因子：
11.1
通讯作者：
Sancar, A
中科院分区：
文献类型：
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作者：
Reardon, JT;Sancar, A
DNA-蛋白质交联是相对常见的DNA损伤，其在DNA的生理加工过程中通过复制和重组蛋白、通过碱基切除修复酶的副反应以及通过细胞暴露于双功能DNA损伤剂如铂化合物而形成。病理性DNA-蛋白质交联在人体中修复的机制尚不清楚。在这项研究中，我们研究了人类切除核酸酶识别和修复蛋白质-DNA和寡肽-DNA交联的机制。在我们的测定条件下，人核苷酸切除修复系统不能以可检测的水平去除与DNA交联的16-kDa蛋白质。然而，与DNA骨架交联的4-aa和12-aa长的寡肽可以被人切除核酸酶的一些损伤识别因子以中等选择性识别，并以相对有效的速率从DNA中切除。我们的数据表明，如果加上蛋白水解降解的交联蛋白，人类切除核酸酶可能是主要的酶系统，用于消除蛋白质-DNA交联的基因组。
DNA-protein crosslinks are relatively common DNA lesions that form during the physiological processing of DNA by replication and recombination proteins, by side reactions of base excision repair enzymes, and by cellular exposure to bifunctional DNA-damaging agents such as platinum compounds. The mechanism by which pathological DNA-protein crosslinks are repaired in humans is not known. In this study, we investigated the mechanism of recognition and repair of protein-DNA and oligopeptide-DNA crosslinks by the human excision nuclease. Under our assay conditions, the human nucleotide excision repair system did not remove a 16-kDa protein crosslinked to DNA at a detectable level. However, 4- and 12-aa-long oligopeptides crosslinked to the DNA backbone were recognized by some of the damage recognition factors of the human excision nuclease with moderate selectivity and were excised from DNA at relatively efficient rates. Our data suggest that, if coupled with proteolytic degradation of the crosslinked protein, the human excision nuclease may be the major enzyme system for eliminating protein-DNA crosslinks from the genome.