Y-family DNA polymerase-independent gap-filling translesion synthesis across aristolochic acid-derived adenine adducts in mouse cells.
Y-family DNA polymerase-independent gap-filling translesion synthesis across aristolochic acid-derived adenine adducts in mouse cells.
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DOI：
10.1016/j.dnarep.2016.07.003
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发表时间：
2016-10
期刊：
影响因子：
3.8
通讯作者：
Moriya, Masaaki
中科院分区：
文献类型：
--
作者：
Hashimoto, Keiji;Bonala, Radha;Johnson, Francis;Grollman, Arthur P.;Moriya, Masaaki
当复制性聚合酶被DNA损伤阻断时，转录DNA合成（TLS）起作用。为了研究哺乳动物TLS的机制，我们采用了一个质粒携带一个单一的7-（脱氧腺苷-N6-基）-马兜铃内酰胺I（dA-AL-I）加合物，这是由人类致癌物马兜铃酸I，和基因工程小鼠胚胎成纤维细胞产生。这种损伤以高频率诱导A到T颠换。Polh、Poli和Polk基因的同时敲除不影响TLS效率或dA-AL-I的编码性质，表明未知的DNA聚合酶可以有效地催化与加合物相对的核苷酸插入和随后的延伸。类似地，Rev 1基因的敲除对TLS没有显著影响。然而，敲除Rev 31基因（编码polypeptide的催化亚基），可显著抑制TLS并消除dA-AL-I至T的颠换。这些结果支持了Rev 1对于哺乳动物细胞中poll的细胞TLS功能不是必需的这一观点。此外，dA-AL-I到T颠换的频率受到序列背景的影响，这表明TLS至少部分地有助于在马兜铃酸诱导的癌症中观察到的突变热点和冷点的形成。
Translesion DNA synthesis (TLS) operates when replicative polymerases are blocked by DNA lesions. To investigate the mechanism of mammalian TLS, we employed a plasmid bearing a single 7-(deoxyadenosine-N6-yl)-aristolactam I (dA-AL-I) adduct, which is generated by the human carcinogen, aristolochic acid I, and genetically engineered mouse embryonic fibroblasts. This lesion induces A to T transversions at a high frequency. The simultaneous knockouts of the Polh, Poli and Polk genes did not influence the TLS efficiency or the coding property of dA-AL-I, indicating that an unknown DNA polymerase(s) can efficiently catalyze the insertion of a nucleotide opposite the adduct and subsequent extension. Similarly, knockout of the Rev1 gene did not significantly affect TLS. However, knockout of the Rev3l gene, coding for the catalytic subunit of polζ, drastically suppressed TLS and abolished dA-AL-I to T transversions. The results support the idea that Rev1 is not essential for the cellular TLS functions of polζ in mammalian cells. Furthermore, the frequency of dA-AL-I to T transversion was affected by a sequence context, suggesting that TLS, at least in part, contributes to the formation of mutational hot and cold spots observed in aristolochic acid-induced cancers.
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阿里斯洛胆酸，主要代谢产物及相关化合物的总合成。
影响因子：
4.1
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.0605247103
发表时间：
2006-11-28
影响因子：
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作者：
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通讯作者：
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影响因子：
16
作者：
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