Andrei Chabes - Professor

Head of Department


dNTPs and maintenance of genome stability

The four dNTPs (dATP, dTTP, dCTP, and dGTP) are the building blocks of DNA. A balanced supply and a correct overall concentration of dNTPs are key prerequisites for faithful genome replication. These requirements, along with the fact that the concentrations of dNTPs fluctuate during the cell cycle, mean that the production of dNTPs must be tightly regulated through multiple mechanisms.

We are investigating (i) how the genome integrity checkpoint regulates the concentration of dNTPs and how dNTPs regulate the activation of the genome integrity checkpoint, and (ii) how imbalanced dNTP pools affect the fidelity of replication and genome stability and how different replication errors are recognized and repaired. We hope to understand how metabolic changes in the dNTP pool balance affect aging, the development of cancer, and other genetic disorders.

Group members:

Senior scientists/Post Docs:
Sushma Sharma

Ph.D. students:
Phong Tran

Research assistants:
Anna Karin Nilsson

Full publication list in PubMed

Selected publications

Saitoh, S., Chabes, A., McDonald, W.H., Thelander, L., Yates, J.R., & Russell, P. (2002). Cid13 is a cytoplasmic poly(A) polymerase that regulates ribonucleotide reductase mRNA. Cell 109, 563-573.

Chabes, A., Georgieva, B., Domkin, V., Zhao X., Rothstein, R., & Thelander, L. (2003). Survival after DNA damage in budding yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase. Cell 112, 391-401.

Chabes, A., & Stillman, B. (2007). Constitutively high dNTP concentration inhibits cell cycle progression and the DNA damage checkpoint in yeast Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. U S A. 104, 1183-1188

Sabouri, N., Viberg, J., Goyal, D.K., Johansson, E., & Chabes, A. (Epub 2008 Sep 4). Evidence for lesion bypass by yeast replicative DNA polymerases during DNA damage. Nucleic Acids Res. 36, 5660-5667.

Nick McElhinny, S.A., Watts, B., Kumar, D., Watt, D., Lundström, E.B., Burgers, P.M.J., Johansson, E., Chabes, A., & Kunkel, T.A. (Epub 2010 Mar 1). Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases. Proc Natl Acad Sci U S A. 107, 4949-4954.

Kumar, D., Viberg, J., Nilsson, A.K., & Chabes, A. (Epub 2010 Mar 9). Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res, 38, 3975-3983.

Nick McElhinny, S.A., Kumar, D., Clark, A.B., Watt, D.L., Watts, B.E., Lundström, E.B., Johansson, E., Chabes, A., & Kunkel, T.A. (Epub 2010 Aug 22) Genome instability due to ribonucleotide incorporation into DNA. Nature Chemical Biology; 6, 774-781.

Kumar, D., Abdulovic, A.L., Viberg, J., Nilsson, A.K., Kunkel, T.A., & Chabes, A. (E pub 2010 Oct 20) Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Res. 39, 1360-1371.

Deem, A., Keszthelyi, A., Blackgrove, T., Vayl, A., Coffey, B., Mathur, R., Chabes, A., & Malkova, A. (2011 Epub 15 Feb) Break-induced replication is highly mutagenic. PLoS Biology. 9(2):e1000594.

Rossmann, M.P., Luo, W., Tsaponina, O., Chabes, A., & Stillman, B. (2011 Epub Apr 7) A common telomeric gene silencing assay is affected by nucleotide metabolism. Mol. Cell. 42, 127-136.

Johansson, E., Speck, C., & Chabes, A. (2011 Epub 27 Apr). A top-down view on DNA replication and recombination from 9,000 feet above sea level. Genome Biology, 12:304.

Tsaponina, O., Barsoum, E., Åström, S.U., & Chabes, A. (2011 Epub May 5) Ixr1 is required for the expression of the ribonucleotide reductase Rnr1 and maintenance of dNTP pools. PLoS Genetics. 7(5): e1002061. Article

Williams, J.S., Smith, D.J., Marjavaara, L., Lujan, S.A., Chabes, A. & Kunkel, T.A. (Epub 2013 Mar 7). Topoisomerase 1-mediated Removal of Ribonucleotides from Nascent Leading Strand DNA. Mol Cell 49, 1010-1015.

Tsaponina, O. & Chabes, A. (2013) Pre-activation of the genome integrity checkpoint increases increases DNA damage tolerance. Nucleic Acids Res. 41:10371-8.Article

Domkin, V. & Chabes, A. (2014 ) Phosphines are ribonucleotide reductase reductants that act via C-terminal cysteines similar to thioredoxins and glutaredoxins. Sci Rep. doi: 10.1038/srep05539

Lin, C.Y., Wu, M.Y., Gay, S., Marjavaara, L., Lai, M.S., Hsiao, W.C., Hung, S.H., Tseng, H.Y., Wright, D.E., Wang, C.Y., Hsu, G.S., Devys, D.,Chabes, A. & Kao, C.F. (2014) H2B Mono-ubiquitylation Facilitates Fork Stalling and Recovery during Replication Stress by Coordinating Rad53 Activation and Chromatin Assembly. PLoS Genet. 2014 Oct 2;10(10):e1004667.

Buckland, R.J., Watt, D.L., Chittoor, B., Nilsson, A.K., Kunkel, T.A. & Chabes, A. (2014) Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity. PLoS Genet. 2014 Dec 4; 10(12): e1004846.

Williams, J.S., Clausen, A.R., Lujan, S.A., Marjavaara, L., Clark, A.B., Burgers, P.M., Chabes, A., & Kunkel, T.A. Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific. Nature Struct Mol Biol. 2015 Mar 9. doi: 10.1038/nsmb.2989.

Watt, D.L., Buckland, R.J., Lujan, S.A., Kunkel, T.A. & Chabes, A. (2016) Genome-wide analysis of the specificity and mechanisms of replication infidelity driven by imbalanced dNTP pools Nucleic Acids Res. 44:1669-80.

Rentoft, M., Lindell, K., Tran, P., Chabes, A.L., Buckland, R.J., Watt, D.L., Marjavaara, L., Nilsson, A.K., Melin, B., Trygg, J., Johansson, E. & Chabes, A. (2016) Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1519128113

Schmidt TT, Reyes G, Gries K, Ceylan CÜ, Sharma S, Meurer M, Knop M, Chabes A, Hombauer H. (2017) Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1618714114.

Wanrooij PH, Engqvist MKM, Forslund JME, Navarrete C, Nilsson AK, Sedman J, Wanrooij S, Clausen AR, Chabes A. (2017) Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1713085114.

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Andrei Chabes

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Umeå University
Medical Biochemistry and Biophysics
SE-901 87 Umeå, SWEDEN 

Visiting Address
KBC-building, 6th floor

Tel:  +46 90 786 5937

Fax:  +46 90 786 9795

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