A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3,N4-ethenocytosine.
A novel role for transcription-coupled nucleotide excision repair for the in vivo repair of 3,N4-ethenocytosine.
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DOI：
10.1093/nar/gkx015
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发表时间：
2017-04-07
影响因子：
14.9
通讯作者：
Samson LD
中科院分区：
文献类型：
--
作者：
Chaim IA;Gardner A;Wu J;Iyama T;Wilson DM 3rd;Samson LD
乙烯基（ε）DNA碱基加合物是通过与脂质过氧化（LPO）产物反应而内源性产生的高度致突变性损伤。促癌性疾病（如炎症）可诱导持续的氧化应激和LPO增加，导致ε-加合物在不同组织中蓄积。使用最近描述的荧光多重宿主细胞再激活测定，我们表明，携带位点特异性3，N4-乙烯胞嘧啶（εC）的质粒报告基因导致转录阻断。值得注意的是，这种阻断在Cockayne综合征和着色性干皮病患者来源的淋巴母细胞和成纤维细胞中加剧。质粒报告基因的平行RNA-Seq表达分析鉴定了εC的新转录突变特性。我们的研究表明，除了已知的途径，如碱基切除修复，转录偶联核苷酸切除修复的过程中发挥作用，从基因组中去除εC，从而保护细胞和组织免受炎症反应诱导的附带损伤。
Etheno (ε) DNA base adducts are highly mutagenic lesions produced endogenously via reactions with lipid peroxidation (LPO) products. Cancer-promoting conditions, such as inflammation, can induce persistent oxidative stress and increased LPO, resulting in the accumulation of ε-adducts in different tissues. Using a recently described fluorescence multiplexed host cell reactivation assay, we show that a plasmid reporter bearing a site-specific 3,N4-ethenocytosine (εC) causes transcriptional blockage. Notably, this blockage is exacerbated in Cockayne Syndrome and xeroderma pigmentosum patient-derived lymphoblastoid and fibroblast cells. Parallel RNA-Seq expression analysis of the plasmid reporter identifies novel transcriptional mutagenesis properties of εC. Our studies reveal that beyond the known pathways, such as base excision repair, the process of transcription-coupled nucleotide excision repair plays a role in the removal of εC from the genome, and thus in the protection of cells and tissues from collateral damage induced by inflammatory responses.