Cited by 40Cancer Genomics and DiagnosticsDNA Repair MechanismsDNA and Nucleic Acid Chemistry

Guanine holes are prominent targets for mutation in cancer and inherited disease

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Bacolla, Albino, Temiz, Nuri A., Yi, Ming, Ivanic, Joseph, Cer, Regina Z., Donohue, Duncan E., Ball, Edward V., Mudunuri, Uma S. +8 more·2013·PLoS Genetics

Abstract

Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G • C bp in the context of all 64 5'-NGNN-3' motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.

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Authors
Bacolla, A., Temiz, N. A., Yi, M., Ivanic, J., Cer, R. Z., Donohue, D. E., Ball, E. V., Mudunuri, U. S., Wang, G., Jain, A., Volfovsky, N., Luke, B. T., Stephens, R. M., Cooper, D. N., Collins, J. R., & Vasquez, K. M.
Affiliations
  • Frederick National Laboratory for Cancer Research (US)
  • Cardiff University (GB)
  • The University of Texas at Austin (US)
Venue
PLoS Genetics
Published
2013-09-26
Volume
9
Issue
9
Pages
e1003816
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
OpenAlex
W2031397281
Cited by
40
References
104
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 6 · 2014: 4
FWCI
1.52
Type
journal article
Language
en
Open access
Locations
  • PLoS Genetics (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Texas ScholarWorks (Texas Digital Library) (submittedVersion, cc-by)
Funders
  • European Bioinformatics Institute
  • Frederick National Laboratory for Cancer Research (HHSN261200800001E.)
  • Cardiff University
  • National Institutes of Health (#HHSN261200800001E, HHSN261200800001C, CA097175)
  • National Cancer Institute (HHSN261200800001E), CA097175, CA093729, P01CA097175, R01CA093729)
  • Center for Biomedical Informatics and Information Technology, National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
GC base pairs, single base substitution, somatic mutations, germline mutations, genetic disorders, ionization potential, splicing mutation, driver mutations, passenger mutations
MeSH terms
DNA, Neoplasm, Guanine, Humans, Models, Molecular, Neoplasms, Germ-Line Mutation, Computational Biology, Amino Acid Substitution, Genetic Diseases, Inborn, Nucleotide Motifs

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