DNA Repair Mechanisms and Cancer

Junior Research Group DNA Repair Mechanisms and Cancer

Dr. Hans Hombauer

DNA replication fidelity and repair. Three important aspects that contribute to DNA replication fidelity: 1) dNTP pools, 2) base selectivity and proofreading and 3) post-replicative mismatch repair system.
© dkfz.de

The maintenance of genome integrity represents an important challenge for every living organism. A variety of environmental factors (e.g. chemicals, radiation, etc) as well as others intrinsic to cellular metabolism (e.g. oxidative damage, DNA replication errors) are frequently damaging the information contained within the DNA.
According to recent studies two-thirds of all mutations identified in human cancers are associated to DNA replication errors, whereas one-third is due to environmental factors or hereditary components. The fidelity of DNA replication depends on the nucleotide selectivity and proofreading activity of DNA polymerases, as well as on the postreplicative DNA mismatch repair (MMR) system. Mutations (or epigenetic silencing) affecting MMR genes result in mutator phenotypes and early onset of cancer, as reported in Lynch Syndrome patients. Similarly, mutations in the proofreading domain of DNA polymerases have been associated to increased mutator phenotypes and ovarian/colorectal cancer predisposition.

Our group is interested in the identification and characterization of genes that contribute to genome integrity. We are currently investigating: a) mechanistic aspects of the mismatch repair reaction, b) novel genes that contribute to DNA replication fidelity and c) how alterations of dNTP homeostasis affect DNA replication fidelity. For our studies we make use of Saccharomyces cerevisiae, a simple eukaryotic organism in which many basic cellular processes (e.g. DNA replication and mismatch repair) have been preserved across evolution. In addition, our lab uses mammalian cells to further investigate genes that may potentially be involved in the suppression of mutations and cancer susceptibility syndromes.

Future Outlook

The main aim of our work is the identification and characterization of genes that play a role for genome stability. We anticipate our studies will lead to the identification of novel genetic variants associated to mutator phenotypes and potentially increased cancer predisposition. Hopefully this knowledge will facilitate in the future the diagnostic and treatment of cancer.

Contact

Dr. Hans Hombauer
DNA Repair Mechanisms and Cancer (A310)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 581
69120 Heidelberg
Tel: +49 6221 42 3239

Selected Publications

  • Schmidt, T. T., G. Reyes, K. Gries, C. U. Ceylan, S. Sharma, M. Meurer, M. Knop, A. Chabes and H. Hombauer (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, in press.
  • Goellner, E. M., C. E. Smith, C. S. Campbell, H. Hombauer, A. Desai, C. D. Putnam and R. D. Kolodner (2014). PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair. Mol Cell 55(2): 291-304.
  • Hombauer, H., A. Srivatsan, C. D. Putnam and R. D. Kolodner (2011). Mismatch repair, but not heteroduplex rejection, is temporally coupled to DNA replication. Science 334(6063): 1713-1716.
  • Hombauer, H., C. S. Campbell, C. E. Smith, A. Desai and R. D. Kolodner (2011). Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates. Cell 147(5): 1040-1053.
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