Nucleotide excision repair of abasic DNA lesions
Nucleotide excision repair of abasic DNA lesions
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DOI：
10.1093/nar/gkz558
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发表时间：
2019-09-19
影响因子：
14.9
通讯作者：
Khobta, Andriy
中科院分区：
文献类型：
--
作者：
Kitsera, Nataliya;Rodriguez-Alvarez, Marta;Khobta, Andriy
无嘌呤/无嘧啶 (AP) 位点是基因组中由许多外源和内源来源产生的一类高度诱变和毒性 DNA 损伤。 AP 损伤的修复主要通过碱基切除途径 (BER) 进行。然而，在 DNA 中形成的化学异质性 AP 损伤中，有些对核酸内切酶 APE1 具有抗性，因此对 BER 具有抵抗力。在这里，我们采用两种类型的报告基因构建体来适应合成的 APE1 抗性 AP 病变，以研究人类细胞中的辅助修复机制。通过对特定位置的 AP 损伤处转录率恢复和转录突变抑制的综合分析，我们证明核苷酸切除修复途径 (NER) 有效去除 BER 抗性 AP 损伤，并显着增强 APE1 敏感损伤的修复。我们的结果进一步表明，核心 NER 组件 XPA 和 XPF 是同样需要的，并且全局基因组 (GG-NER) 和转录偶联 (TC-NER) 子路径都有助于修复。
Apurinic/apyrimidinic (AP) sites are a class of highly mutagenic and toxic DNA lesions arising in the genome from a number of exogenous and endogenous sources. Repair of AP lesions takes place predominantly by the base excision pathway (BER). However, among chemically heterogeneous AP lesions formed in DNA, some are resistant to the endonuclease APE1 and thus refractory to BER. Here, we employed two types of reporter constructs accommodating synthetic APE1-resistant AP lesions to investigate the auxiliary repair mechanisms in human cells. By combined analyses of recovery of the transcription rate and suppression of transcriptional mutagenesis at specifically positioned AP lesions, we demonstrate that nucleotide excision repair pathway (NER) efficiently removes BER-resistant AP lesions and significantly enhances the repair of APE1-sensitive ones. Our results further indicate that core NER components XPA and XPF are equally required and that both global genome (GG-NER) and transcription coupled (TC-NER) subpathways contribute to the repair.