小柯机器人

英国爱丁堡大学Andrew P. Jackson，Martin S. Taylor和Martin A. M. Reijns共同合作，取得重要研究进展。他们研究发现癌症和生殖系统中TOP1转录相关的基因诱变特征。该项研究成果在线发表于2022年2月9日出版的《自然》杂志上。

在这里，研究人员发现ID4（以2~5个碱基对的短片段缺失为特征，是一种未知病因的癌症indel突变标志）是由于转录相关的过程诱导的基因突变。研究人员证明，哺乳动物的核糖核苷酸切除修复缺陷与ID4特征相关，在TNT序列基序上发生突变，暗示基因组嵌入核糖核苷酸位点的拓扑异构酶1 (TOP1)活性可能作为机制基础。这种TOP1介导的缺失发生在癌症的体细胞上，ID-TOP1特征也在生理环境中被发现，有助于生殖系中基因从头产生indel突变。因此，尽管拓扑异构酶通过减轻拓扑压力来防止基因组不稳定性，但它们的活性也可能是人类基因组突变的重要来源。

据了解，基因突变图谱是由许多生命过程塑造的。基因区域易受突变影响，但会优先受到转录偶联修复过程的保护。在微生物中，转录已被证明具有基因诱变性。然而，转录相关的基因诱变在高等真核生物中的影响仍有待确定。

附：英文原文

Title: Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

Author: Reijns, Martin A. M., Parry, David A., Williams, Thomas C., Nadeu, Ferran, Hindshaw, Rebecca L., Rios Szwed, Diana O., Nicholson, Michael D., Carroll, Paula, Boyle, Shelagh, Royo, Romina, Cornish, Alex J., Xiang, Hang, Ridout, Kate, Schuh, Anna, Aden, Konrad, Palles, Claire, Campo, Elias, Stankovic, Tatjana, Taylor, Martin S., Jackson, Andrew P.

Issue&Volume: 2022-02-09

Abstract: The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.

DOI: 10.1038/s41586-022-04403-y

Source: https://www.nature.com/articles/s41586-022-04403-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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