Guanine holes are prominent targets for mutation in cancer and inherited disease
Open accessAbstract
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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Zhang, W., Bouffard, G. G., Wallace, S. S., Bond, J. P., & Program, N. C. S. (2007) · Journal of Molecular Evolution · doi:10.1007/s00239-007-9000-5 · Cited by 26 · see citing works
Baele, G., de Peer, Y. V., & Vansteelandt, S. (2008) · Systematic Biology · doi:10.1080/10635150802422324 · Cited by 25 · see citing works
Origin of the Heterogeneous Distribution of the Yield of Guanyl Radical in UV Laser Photolyzed DNA
Angelov, D., Beylot, B., & Spassky, A. (2004) · Biophysical Journal · doi:10.1529/biophysj.104.049015 · Cited by 22 · see citing works
Yi, M., Mudunuri, U. S., Che, A., & Stephens, R. M. (2009) · BMC Bioinformatics · doi:10.1186/1471-2105-10-200 · Cited by 20 · see citing works
Self-citationMadison, A. L., Perez, Z. A., To, P., Maisonet, T., Rios, E. V., Trejo, Y., Ochoa-Paniagua, C., Reno, A., & Stemp, E. D. A. (2012) · Biochemistry · doi:10.1021/bi201087q · Cited by 18 · see citing works
SNP-based prediction of the human germ cell methylation landscape
Xie, H., Wang, M., Bischof, J. M., Bonaldo, M. F., & Soares, M. B. (2009) · Genomics · doi:10.1016/j.ygeno.2009.01.005 · Cited by 16 · see citing works
Ivanov, D. K., Hamby, S. E., Stenson, P. D., Phillips, A. D., Kehrer-Sawatzki, H., Cooper, D. N., & Chuzhanova, N. A. (2011) · Human Mutation · doi:10.1002/humu.21483 · Cited by 16 · see citing works
Self-citationHole Traps in DNA Calculated with Exponential Electron−Lattice Coupling
Park, J. H., Choi, H.-Y., & Conwell, E. M. (2004) · The Journal of Physical Chemistry B · doi:10.1021/jp046968p · Cited by 15 · see citing works
Yokojima, S., Yoshiki, N., Yanoi, W., & Okada, A. (2009) · The Journal of Physical Chemistry B · doi:10.1021/jp9054582 · Cited by 13 · see citing works
Baele, G., de Peer, Y. V., & Vansteelandt, S. (2009) · BMC Evolutionary Biology · doi:10.1186/1471-2148-9-87 · Cited by 12 · see citing works
Large-scale inference of the point mutational spectrum in human segmental duplications
Nakken, S., Rødland, E. A., Rognes, T., & Hovig, E. J. (2009) · BMC Genomics · doi:10.1186/1471-2164-10-43 · Cited by 11 · see citing works
The Role of One‐Electron Reduction of Lipid Hydroperoxides in Causing DNA Damage
Crean, C. W., Shao, J., Yun, B. H., Geacintov, N. E., & Shafirovich, V. (2009) · Chemistry - A European Journal · doi:10.1002/chem.200900500 · Cited by 8 · see citing works
Stability of the guanine-cytosine radical cation in DNA base pairs triplets
Hutter, M. C. (2006) · Chemical Physics · doi:10.1016/j.chemphys.2006.01.007 · Cited by 8 · see citing works
Increased complexity of gene structure and base composition in vertebrates
Wu, Y., Yuan, H., Tan, S., Chen, J., Tian, D., & Yang, H. (2011) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2011.06.004 · Cited by 4 · see citing works
Flagged first, then by citations
1 of the 104 references couldn’t be matched to a known paper.
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Stenson, P. D., Mort, M. E., Ball, E. V., Evans, K., Hayden, M., Heywood, S., Hussain, M., Phillips, A. D., & Cooper, D. N. (2017) · Human Genetics · doi:10.1007/s00439-017-1779-6 · Cited by 1,348 · see citing works
Self-citationHypermutation in human cancer genomes: footprints and mechanisms
Roberts, S. A., & Gordenin, D. A. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3816 · Cited by 397 · see citing works
Kim, H.-Y., Lee, K., Kim, S., Kwon, Y., Chun, Y., & Choi, H. (2016) · Oncotarget · doi:10.18632/oncotarget.11560 · Cited by 123 · see citing works
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Pantsar, T., Rissanen, S., Dauch, D., Laitinen, T., Vattulainen, I., & Poso, A. (2018) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1006458 · Cited by 85 · see citing works
Du, X., Gertz, E. M., Wójtowicz, D., Zhabinskaya, D., Levens, D., Benham, C. J., Schäffer, A. A., & Przytycka, T. M. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku921 · Cited by 57 · see citing works
Mechanisms of Base Substitution Mutagenesis in Cancer Genomes
Bacolla, A., Cooper, D., & Vasquez, K. M. (2014) · Genes · doi:10.3390/genes5010108 · Cited by 52 · see citing works
Self-citationCancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction
Bacolla, A., Ye, Z., Ahmed, Z., & Tainer, J. A. (2019) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2019.03.004 · Cited by 50 · see citing works
Self-citationRotunno, M., McMaster, M. L., Boland, J. F., Bass, S. E., Zhang, X., Burdett, L. A., Hicks, B. D., Ravichandran, S., Luke, B. T., Yeager, M., et al. (2016) · Haematologica · doi:10.3324/haematol.2015.135475 · Cited by 40 · see citing works
Self-citationReplication stress at microsatellites causes DNA double-strand breaks and break-induced replication
Gadgil, R., Romer, E. J., Goodman, C., Rider, S., Damewood, F. J., Barthelemy, J., Shin-ya, K., Hanenberg, H., & Leffak, M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013495 · Cited by 32 · see citing works
Tiek, D. M., Erdogdu, B., Razaghi, R., Lu, J., Sadowski, N., Alamillo‐Ferrer, C., Hogg, J. R., Haddad, B. R., Drewry, D. H., Wells, C. I., et al. (2022) · Science Advances · doi:10.1126/sciadv.abn3471 · Cited by 34 · see citing works
Genomic Approaches to DNA repair and Mutagenesis
Wyrick, J. J., & Roberts, S. A. (2015) · DNA Repair · doi:10.1016/j.dnarep.2015.09.018 · Cited by 32 · see citing works
Contributing factors to the oxidation-induced mutational landscape in human cells
Cordero, C., Mehta, K. P. M., Weaver, T., Ling, J. A., Freudenthal, B., Cortez, D., & Roberts, S. A. (2024) · Nature Communications · doi:10.1038/s41467-024-55497-z · Cited by 36 · see citing works
A Role for Non‐B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease
Kamat, M., Bacolla, A., Cooper, D. N., & Chuzhanova, N. (2016) · Human Mutation · doi:10.1002/humu.22917 · Cited by 21 · see citing works
Self-citationLocal DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes
Bacolla, A., Zhu, X., Chen, H., Howells, K., Cooper, D. N., & Vásquez, K. M. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv364 · Cited by 22 · see citing works
Self-citationStein, M., & Eckert, K. A. (2021) · Genes · doi:10.3390/genes12111779 · Cited by 20 · see citing works
The somatic autosomal mutation matrix in cancer genomes
Temiz, N. A., Donohue, D. E., Bacolla, A., Vásquez, K. M., Cooper, D. N., Mudunuri, U. S., Ivanic, J., Cer, R. Z., Yi, M., Stephens, R. M., et al. (2015) · Human Genetics · doi:10.1007/s00439-015-1566-1 · Cited by 17 · see citing works
Self-citationOxidative damage within alternative DNA structures results in aberrant mutagenic processing
Zewail‐Foote, M., del Mundo, I. M. A., Klattenhoff, A. W., & Vásquez, K. M. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf066 · Cited by 12 · see citing works
Vandenberg, B. N., Laughery, M. F., Cordero, C., Plummer, D. A., Mitchell, D., Kreyenhagen, J., Albaqshi, F., Brown, A. J., Mieczkowski, P. A., Wyrick, J. J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38255-5 · Cited by 11 · see citing works
Influence of Electron–Holes on DNA Sequence-Specific Mutation Rates
Villagrán, M., Azevedo, R. B. R., & Miller, J. H. (2018) · Genome Biology and Evolution · doi:10.1093/gbe/evy060 · Cited by 12 · see citing works
Exploring the Lower Limit of Target Concentration in Capture‐SELEX Using Guanine as a Model Target
Ding, Y., Zhang, Z., & Liu, J. (2024) · ChemBioChem · doi:10.1002/cbic.202400570 · Cited by 11 · see citing works
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Structure–activity features of purines and their receptors: implications in cell physiopathology
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Relation between DNA ionization potentials, single base substitutions and pathogenic variants
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Normal and impaired charge transport in biological systems
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Drastic promotion of guanine oxidation via electron transfer in Ψ-type DNA
Sakurai, S., Esumi, M., & Tanaka, M. (2019) · Chemical Communications · doi:10.1039/c9cc02255d · Cited by 6 · see citing works
Tanaka, M., Matsumoto, T., & Iida, H. (2018) · Organic & Biomolecular Chemistry · doi:10.1039/c8ob02003e · Cited by 5 · see citing works
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Nanomolar Fluorescent Detection of Guanine Using Tin Porphyrin
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MoCoLo: a testing framework for motif co-localization
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Estimating the Vertical Ionization Potential of Single-Stranded DNA Molecules
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Grand Celebration: 10th Anniversary of the Human Genome Project
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Linking somatic mutations in cancer to the electronic properties of DNA
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Delocalized DNA holes imprint mutation position in mismatch-repair-deficient cancersPreprint
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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)
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-09-26
- Volume
- 9
- Issue
- 9
- Pages
- e1003816
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3784513
- 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
- gold
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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