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Transcriptional mutagenesis dramatically alters genome-wide p53 transactivation landscape

Shuo Liang1, Monika Ezerskyte2, Jingwen Wang3

  • 1Unit of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.

Scientific Reports
|August 13, 2020
PubMed

Insights

DNA lesions like O6-methylguanine cause transcriptional mutagenesis (TM), altering p53 protein function and gene expression. This study reveals TM

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA lesions can increase transcriptional error rates, leading to transcriptional mutagenesis (TM).
  • TM can alter protein function and impact cellular processes.
  • O6-methylguanine (O6-meG) is a DNA lesion that can cause misincorporation during transcription.

Purpose of the Study:

  • To investigate the effect of O6-methylguanine (O6-meG) on transcription and p53 transactivation activity.
  • To determine the genome-wide levels of TM and its impact on p53 DNA binding and gene expression.
  • To analyze the consequences of TM on p53 target gene regulation.

Main Methods:

  • Utilized RNA sequencing (RNA-seq) to assess genome-wide TM levels and gene expression changes.
  • Quantified uridine misincorporation opposite O6-meG in p53 transcripts.
  • Measured p53 DNA binding activity and analyzed differential gene expression.

Main Results:

  • O6-meG induced significant uridine misincorporation in p53 transcripts (47% at 6h, 18% at 24h).
  • TM reduced p53 DNA binding activity (to 21% and 80% of wild type).
  • TM temporally repressed transactivation of over 100 p53 target genes, including cell cycle and apoptosis regulators, and repressed p53-mediated downregulation of proliferation genes.

Conclusions:

  • Transcriptional mutagenesis, even when focused on a single transcription factor like p53, can profoundly alter gene expression programs.
  • TM can diversify cellular phenotypes by modulating gene expression.
  • These findings highlight the significant impact of DNA damage-induced transcriptional errors on cellular function.

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