期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2004077118
关键词
transcription error; mutagenesis; genotoxic stress; DNA damage
资金
- National Center for Genome Analysis Support at Indiana University [NSF ABI-1759906 2018]
- National Institute on Aging Award [R01AG054641]
- American Federation for Aging Research young investigator award in Alzheimer's disease
- Multidisciplinary University Research Initiative Awards from the US Army Research Office [W911NF-09-1-0444]
- NIH [R35-GM122566-01]
- Environmental Toxicology Training Grant by the National Institute of Environmental Health Sciences [T32ES019851]
Research shows that mutagenic compounds not only cause genetic mutations, but are also a powerful source of transcription errors. These errors occur in both dividing and nondividing cells, and sometimes greatly exceed the number of mutations in the genome. Additionally, DNA repair is crucial in mitigating transcriptional mutagenesis after exposure to mutagens.
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.
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