Arrest of human mitochondrial RNA polymerase transcription by the biological aldehyde adduct of DNA, M1dG.
Arrest of human mitochondrial RNA polymerase transcription by the biological aldehyde adduct of DNA, M1dG.
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DOI：
10.1093/nar/gkq656
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发表时间：
2010-11
影响因子：
14.9
通讯作者：
Arnold JJ
中科院分区：
文献类型：
--
作者：
Cline SD;Lodeiro MF;Marnett LJ;Cameron CE;Arnold JJ
生物醛，丙二醛和碱丙烯醛，与DNA反应，形成一个普遍的鸟嘌呤加合物，M1 dG。当与C配对时，M1 dG的环外环向无环N2-OPdG结构打开，但在单链DNA中或与T错配时保持闭合。M1 dG是核苷酸切除修复（NER）的靶点;然而，NER在线粒体中不存在。用纯化的人线粒体RNA聚合酶（POLRMT）和转录因子mtTFA和mtTFB 2的体外转录系统来确定M1 dG对POLRMT延伸的影响。DNA模板含有一个单一的加合物，相对于POLRMT的轻链（LSP）或重链（HSP 1）启动子下游的C或T。转录链中的M1 dG阻滞了60-90%的POLRMT延伸复合物，当与T相对时，加合物的阻滞作用更大。POLRMT在LSP起始后对N2-OPdG和M1 dG更敏感，这表明POLRMT复合物的功能存在启动子特异性差异。M1 dG的闭环类似物PdG阻断了≥95%的源自任一启动子的转录物，无论碱基配对如何，并且转录物在加合物处停滞后仍与POLRMT复合物结合。这项工作表明，线粒体DNA中的持续M1 dG加合物阻碍了线粒体基因的转录。
The biological aldehydes, malondialdehyde and base propenal, react with DNA to form a prevalent guanine adduct, M1dG. The exocyclic ring of M1dG opens to the acyclic N2-OPdG structure when paired with C but remains closed in single-stranded DNA or when mispaired with T. M1dG is a target of nucleotide excision repair (NER); however, NER is absent in mitochondria. An in vitro transcription system with purified human mitochondrial RNA polymerase (POLRMT) and transcription factors, mtTFA and mtTFB2, was used to determine the effect of M1dG on POLRMT elongation. DNA templates contained a single adduct opposite either C or T downstream of either the light-strand (LSP) or heavy-strand (HSP1) promoter for POLRMT. M1dG in the transcribed strand arrested 60–90% POLRMT elongation complexes with greater arrest by the adduct when opposite T. POLRMT was more sensitive to N2-OPdG and M1dG after initiation at LSP, which suggests promoter-specific differences in the function of POLRMT complexes. A closed-ring analog of M1dG, PdG, blocked ≥95% of transcripts originating from either promoter regardless of base pairing, and the transcripts remained associated with POLRMT complexes after stalling at the adduct. This work suggests that persistent M1dG adducts in mitochondrial DNA hinder the transcription of mitochondrial genes.
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影响因子：
2.7
作者：
Brégeon, D;Doetsch, PW
通讯作者：
Doetsch, PW
影响因子：
11.4
作者：
Charlet-Berguerand, Nicolas;Feuerhahn, Sascha;Egly, Jean Marc
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影响因子：
4.8
作者：
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影响因子：
8
作者：
Hanawalt, PC
通讯作者：
Hanawalt, PC
DOI：
10.1016/s0027-5107(98)00129-8
发表时间：
1998-09-20
影响因子：
2.3
作者：
Kadlubar, FF;Anderson, KE;Bartsch, H
通讯作者：
Bartsch, H