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首页> 外文期刊>Biochemistry >Evidence for a recombination-independent pathway for the repair of DNA interstrand cross-links based on a site-specific study with nitrogen mustard.
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Evidence for a recombination-independent pathway for the repair of DNA interstrand cross-links based on a site-specific study with nitrogen mustard.

机译：基于氮芥子气的特定站点研究的DNA链间交联修复的非重组途径的证据。

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摘要

DNA-DNA interstrand cross-links are thought to be important for the cytotoxicity of many chemotherapeutic agents. To study this more definitively, adduct site-specific methods are used to construct a plasmid with a single nitrogen mustard interstrand cross-link (inter-HN2-pTZSV28). Replication efficiency (RE = [colonies from (inter-HN2-pTZSV28)/(control with no cross-link)]) is approximately 0.3 following transformation into Escherichia coli, implying that the cross-link is repaired. The commonly accepted pathway for cross-link repair, which involves both nucleotide excision repair (NER) and recombination, is ruled out since RE is approximately 0.3 in a delta recA strain. Non-RecA-directed recombination such as copy-choice is also unlikely. However, NER is involved since RE was approximately 0.02 in strains deficient in NER. Base excision repair is not important since RE is approximately 0.3 in strains deficient in 3-methyladenine DNA glycosylases I and II, FAPY DNA glycosylase, both known apurinic/apyrimidinic endonucleases, or DNA deoxyribophosphodiesterase. Another hypothetical repair pathway hinging on a 5' --> 3' exonuclease activity is unlikely since RE is approximately 0.3 in cells deficient in either the 5' --> 3' exonuclease activities of DNA polymerase I, exonuclease VII, or RecJ. Thus, aside from NER, it is unclear what else participates in this recombination-independent repair pathway, although a pathway involing NER followed by replicative bypass of the lesion is the current working hypothesis. Psoralen interstrand cross-links appear not to be repairable by this second pathway, which may have implications for the relative cytotoxicity of interstrand cross-links from different agents.
机译：DNA-DNA链间交联被认为对许多化学治疗剂的细胞毒性很重要。为了更明确地研究这一点，使用加合物位点特异性方法构建具有单个氮芥子链间交联键（inter-HN2-pTZSV28）的质粒。转化为大肠杆菌后，复制效率（RE = [来自（HN2-pTZSV28中间的菌落）/（无交联的对照）]）约为0.3，这意味着交联得到了修复。由于delta recA菌株中RE约为0.3，因此排除了涉及核苷酸切除修复（NER）和重组的交联修复普遍接受的途径。非RecA定向的重组（如复制选择）也是不太可能的。但是，由于NER缺陷菌株中RE约为0.02，因此涉及NER。碱基切除修复并不重要，因为在3-甲基腺嘌呤DNA糖基化酶I和II，FAPY DNA糖基化酶（均为已知的嘌呤/嘧啶内切核酸酶）或DNA脱氧核糖磷酸二酯酶不足的菌株中，RE约为0.3。依赖于5'-> 3'核酸外切酶活性的另一种假设修复途径不太可能，因为在DNA聚合酶I，核酸外切酶VII或RecJ的5'-> 3'核酸外切酶活性不足的细胞中RE约为0.3。因此，除NER外，尚不清楚其他因素是否参与了这种与重组无关的修复途径，尽管当前的工作假设是NER参与的途径，然后是病灶的复制性旁路。补骨脂素的链间交联似乎无法通过该第二途径修复，这可能与来自不同药物的链间交联的相对细胞毒性有关。

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