Department of Cellular and Molecular Biology, University of Pennsylvania, Philadelphia, PA 19104.
School of Life Sciences, Biodesign Center for Mechanisms of Evolution, Arizona State University, Tempe, AZ 85287.
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1). doi: 10.1073/pnas.2004077118. Epub 2020 Dec 21.
Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.
诱变剂是人类疾病的一个重要来源。通过诱导遗传不稳定性，它们可以加速人类癌症的进化，或者导致遗传性疾病的发展。在这里，我们表明，除了基因突变，诱变剂也是转录错误的一个强大来源。这些错误在分裂和非分裂细胞中同样出现，影响细胞内每一类转录本，并且在某些情况下，大大超过基因组中出现的突变数量。此外，我们揭示了转录错误对诱变剂暴露的反应动力学，并发现 DNA 修复是减轻暴露后转录诱变的必要条件。总的来说，这些观察结果对我们理解人类衰老和疾病中的诱变作用具有深远的影响，并表明 DNA 损伤对人类生理学的影响被大大低估了。
