Andrei Chabes - Professor
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.
Senior scientists/Post Docs:
Anna Lena Chabes
Anna Karin Nilsson
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. (Epub 2013 Sep 17) Pre-activation of the genome integrity checkpoint increases increases DNA damage tolerance. Nucleic Acids Res. doi: 10.1093/nar/gkt820 Article
Domkin, V. & Chabes, A. (Epub 2014 Jul 2) Phosphines are ribonucleotide reductase reductants that act via C-terminal cysteines similar to thioredoxins and glutaredoxins. Sci Rep. doi: 10.1038/srep05539