Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools

Dinesh Kumar, Amy L. Abdulovic, Jörgen Viberg, Anna Karin Nilsson, Thomas A. Kunkel, Andrei Chabes

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

The mechanisms by which imbalanced dNTPs induce mutations have been well characterized within a test tube, but not in vivo. We have examined mechanisms by which dNTP imbalances induce genome instability in strains of Saccharomyces cerevisiae with different amino acid substitutions in Rnr1, the large subunit of ribonucleotide reductase. These strains have different dNTP imbalances that correlate with elevated CAN1 mutation rates, with both substitution and insertion-deletion rates increasing by 10- to 300-fold. The locations of the mutations in a strain with elevated dTTP and dCTP are completely different from those in a strain with elevated dATP and dGTP. Thus, imbalanced dNTPs reduce genome stability in a manner that is highly dependent on the nature and degree of the imbalance. Mutagenesis is enhanced despite the availability of proofreading and mismatch repair. The mutations can be explained by imbalanced dNTP-induced increases in misinsertion, strand misalignment and mismatch extension at the expense of proofreading. This implies that the relative dNTP concentrations measured in extracts are truly available to a replication fork in vivo. An interesting mutational strand bias is observed in one rnr1 strain, suggesting that the S-phase checkpoint selectively prevents replication errors during leading strand replication. The Author(s) 2010. Published by Oxford University Press.2010This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Original languageEnglish (US)
Pages (from-to)1360-1371
Number of pages12
JournalNucleic Acids Research
Volume39
Issue number4
DOIs
StatePublished - Mar 1 2011

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Mutagenesis
Genomic Instability
Licensure
Mutation
S Phase Cell Cycle Checkpoints
Ribonucleotide Reductases
DNA Mismatch Repair
Mutation Rate
Amino Acid Substitution
Reproduction
Saccharomyces cerevisiae
2'-deoxycytidine 5'-triphosphate
deoxyguanosine triphosphate
thymidine 5'-triphosphate

ASJC Scopus subject areas

  • Genetics

Cite this

Kumar, D., Abdulovic, A. L., Viberg, J., Nilsson, A. K., Kunkel, T. A., & Chabes, A. (2011). Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Research, 39(4), 1360-1371. https://doi.org/10.1093/nar/gkq829

Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. / Kumar, Dinesh; Abdulovic, Amy L.; Viberg, Jörgen; Nilsson, Anna Karin; Kunkel, Thomas A.; Chabes, Andrei.

In: Nucleic Acids Research, Vol. 39, No. 4, 01.03.2011, p. 1360-1371.

Research output: Contribution to journalArticle

Kumar, D, Abdulovic, AL, Viberg, J, Nilsson, AK, Kunkel, TA & Chabes, A 2011, 'Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools', Nucleic Acids Research, vol. 39, no. 4, pp. 1360-1371. https://doi.org/10.1093/nar/gkq829
Kumar, Dinesh ; Abdulovic, Amy L. ; Viberg, Jörgen ; Nilsson, Anna Karin ; Kunkel, Thomas A. ; Chabes, Andrei. / Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. In: Nucleic Acids Research. 2011 ; Vol. 39, No. 4. pp. 1360-1371.
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