Disease Mechanisms, MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
Biomedical Genomics, MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
Nature. 2022 Feb;602(7898):623-631. doi: 10.1038/s41586-022-04403-y. Epub 2022 Feb 9.
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair. In microorganisms, transcription has been demonstrated to be mutagenic; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology 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 stress, their activity may also be an important source of mutations in the human genome.
突变景观是由许多过程塑造的。基因区域容易发生突变，但优先受到转录偶联修复的保护。在微生物中，转录已被证明具有诱变作用；然而，转录相关诱变在高等真核生物中的影响仍有待确定。在这里，我们表明 ID4-一种由短（2 到 5 个碱基对）缺失组成的未知病因的癌症插入缺失（indel）突变特征-是由于转录相关诱变过程。我们证明哺乳动物中缺陷的核糖核苷酸切除修复与 ID4 特征相关，突变发生在 TNT 序列基序上，暗示拓扑异构酶 1（TOP1）在基因组嵌入核糖核苷酸的部位的活性是一种机制基础。这种 TOP1 介导的缺失在癌症中发生在体细胞中，ID-TOP1 特征也存在于生理环境中，导致生殖系中新的基因内 indel 突变。因此，尽管拓扑异构酶通过缓解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中突变的重要来源。
