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Mutagenic consequences of cytosine alterations site-specifically embedded in the human genome

Akira Sassa1, Yuki Kanemaru1,2, Nagisa Kamoshita1

  • 1Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501 Japan.

Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society
|September 3, 2016
PubMed
Abstract

Insights

Modified cytosine bases, specifically 5-methylcytosine and 5-bromocytosine, significantly increase the risk of mutations in the human genome upon deamination. This highlights their pro-mutagenic nature.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Cytosine modifications like methylation and halogenation in CpG dinucleotides can lead to mutations and mutational hotspots.
  • The Tracing DNA Adducts in Targeted Mutagenesis (TATAM) system was developed to analyze mutations induced by DNA modifications in the human genome.

Purpose of the Study:

  • To investigate the genomic consequences of directly introducing various altered cytosine residues into the human genome.
  • To understand the mutagenesis of cytosine modifications using the TATAM system.

Main Methods:

  • Site-specific introduction of modified/damaged bases into intron 4 of thymidine kinase genes in human lymphoblastoid cells.
  • Utilizing the TATAM system to analyze mutations induced by specific cytosine modifications.

Main Results:

  • Deamination of 5-methylcytosine and 5-bromocytosine resulted in pairings with guanine that were highly pro-mutagenic.
  • Compared to normal cytosine deamination (uracil-guanine pairing), modified cytosine deamination showed a significantly higher mutagenic potential.

Conclusions:

  • The deamination of 5-methylcytosine and 5-bromocytosine dramatically enhances mutagenic potential in the human genome.
  • These findings underscore the significant role of modified cytosine deamination in driving genomic instability and mutation formation.
Keywords:
DeaminationGene targetingMutagenesisMutagenic potential

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