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首页> 外文期刊>Journal of Molecular Biology >Ribonucleotides and Transcription-Associated Mutagenesis in Yeast
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Ribonucleotides and Transcription-Associated Mutagenesis in Yeast

机译：酵母中的核糖核苷酸和转录相关的诱变

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Abstract High levels of transcription stimulate mutation rates in microorganisms, and this occurs primarily through an enhanced accumulation of DNA damage. The major source of transcription-associated damage in yeast is Topoisomerase I (Top1), an enzyme that removes torsional stress that accumulates when DNA strands are separated. Top1 relieves torsional stress by nicking and resealing one DNA strand, and some Top1-dependent mutations are due to trapping and processing of the covalent cleavage intermediate. Most, however, reflect enzyme incision at ribonucleotides, which are the most abundant noncanonical component of DNA. In either case, Top1 generates a distinctive mutation signature composed of short deletions in tandem repeats; in the specific case of ribonucleotide-initiated events, mutations reflect sequential cleavage by the enzyme. Top1-dependent mutations do not require highly activated transcription, but their levels are greatly increased by transcription, which partially reflects an interaction of Top1 with RNA polymerase. Recent studies have demonstrated that Top1-dependent mutations exhibit a strand bias, with the nature of the bias differing depending on the transcriptional status of the underlying DNA. Under low-transcription conditions, most Top1-dependent mutations arise in the context of replication and reflect incision at ribonucleotides incorporated during leading-strand synthesis. Under high-transcription conditions, most Top1-dependent events arise when the enzyme cleaves the non-transcribed strand of DNA. In addition to increasing genetic instability in growing cells, Top1 activity in transcriptionally active regions may be a source of mutations in quiescent cells. Graphical Abstract Transcription stimulates mutagenesis through enhanced damage to DNA ribonucleotide-dependent deletions associated with transcription that reflect sequential Top1 cleavage of the non-transcribed DNA strand. Display Omitted Highlights ? Transcription increases damage and elevates mutations in the DNA template. ? Transcription produces a distinctive deletion signature that requires Top1 activity. ? Most Top1-dependent mutations initiate at ribonucleotides embedded in DNA. ? Ribonucleotide-dependent deletions occur via sequential Top1 cleavage of DNA.
机译：转录的抽象水平高刺激微生物突变率，并且这通过DNA损伤的增强累积主要发生。在酵母中转录相关的损伤的主要来源是拓扑异构酶I（TOP1），其去除扭转应力，其累积当DNA链被分离的酶。 TOP1由切口和再密封一个DNA链减轻扭转应力，而一些TOP1依赖性突变是由于捕获和共价裂解中间的处理。但是，大多数反映核糖核苷酸，其是DNA最丰富的非经典部件酶切口。在任一情况下，TOP1生成以串联重复短缺失组成的独特的突变签名;在核糖核苷酸发起的事件的具体情况下，突变反映由酶顺序裂解。 TOP1相关的突变并不需要高度活化转录，但他们的水平都大大增加了转录，这部分反映了TOP1与RNA聚合酶的相互作用。最近的研究表明，TOP1相关的突变表现出链偏差，与偏置依赖于底层的DNA的转录状态不同的性质。在低转录条件下，大多数TOP1依赖性突变出现在复制的情况下和在反映过程中导致链合成掺入核糖核苷酸切口。在高转录的条件下，最TOP1依赖性事件出现时的酶裂解DNA的非转录链。除了在生长的细胞增加的遗传不稳定性，在转录活性区域TOP1活性可以是在静息细胞突变的来源。通过增强反映非转录的DNA链的顺序TOP1裂解与转录相关的DNA的核糖核苷酸依赖性缺失损害图形摘要转录可以刺激诱变。显示中省略亮点？转录增加了DNA模板损伤和提升突变。还是转录产生需要TOP1活动与众不同删除签名。还是大多数TOP1依赖突变引发的嵌入DNA核糖核苷酸。还是核糖核苷酸依赖性缺失通过DNA顺序TOP1裂解发生。

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