DNA Repair Mechanisms and Cancer

Junior Research Group DNA Repair Mechanisms and Cancer

Dr. Hans Hombauer

Life-cell imaging of Mismatch repair protein complexes Mlh1-Pms1 in S. cerevisiae. Pms1 tagged with GFP (green) forms nuclear foci (arrow). The nuclear pore protein Nic96 tagged with mCherry (in red) was used as nuclear marker.
© dkfz.de

The maintenance of genome integrity represents an important challenge for every living organism. A variety of environmental factors (chemicals, radiation, viruses, etc.), but also others intrinsic to cellular metabolism (e.g. oxidative species or DNA replication errors) are frequently damaging the information contained within the DNA. Alterations in the genetic information (mutations) are the cause of several human diseases, including cancer. Not surprisingly, living organisms have developed a variety of DNA repair mechanisms that act in concert to safeguard the stability of the genome.

Our research group investigates the molecular mechanisms that allow DNA repair pathways to preserve genome stability, specifically the DNA mismatch repair (MMR) pathway. This pathway is a post-replicative repair mechanism that increases DNA replication fidelity (to about three orders of magnitude) by recognizing errors introduced during DNA replication, and promoting repair by an excision and re-synthesis mechanism. Mutations that inactivate MMR result in Lynch Syndrome, also referred to as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). This syndrome is characterized by genome instability, especially at repetitive sequences or microsatellites (microsatellite instability or MSI) and early onset of colorectal and other types of cancer.

FUTURE OUTLOOK
We are interested in expanding the mechanistic understanding about the MMR reaction by identifying and characterizing mutations/genes that prevent the accumulation of mutations. To learn more about these processes, we combine genetics, molecular and cell biology approaches in S. cerevisiae and mammalian tissue culture.

Our studies aim to characterize the mechanistic aspects of the MMR reaction, in particular, the MMR repair intermediate Mlh1-Pms1 (Mlh1-Pms2 in humans), which we have identified as active sites of repair in budding yeast. Furthermore, we are interested in identifying and characterizing alternative mechanisms that can result in MMR inactivation, and how specific missense mutations inactivate MMR function in a dominant manner. These studies might reveal why specific MMR missense mutations result in different degrees of cancer manifestation (e.g. early-onset, high penetrance and relapse).

Moreover, our future work aims at identifying and characterizing previously unrecognized genes that affect DNA genome stability. We expect that some of these identified genes will in the future expand our understanding of the mechanisms that can contribute to cancer progression and might provide additional tools for cancer diagnosis.

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

  • Reyes X. et al. (2015). New insights into the mechanism of DNA mismatch repair. Chromosoma, 124(4), 443-462.
  • Campbell C. et al. (2014). Mlh2 is an accessory factor for DNA mismatch repair in Saccharomyces cerevisiae. PLoS Genet, 10(5), e1004327.
  • Hombauer H., et al. (2011). Mismatch repair, but not heteroduplex rejection, is temporally coupled to DNA. Science, 334(6063), 1713–1716.
  • Hombauer H. et al. (2011). Visualization of Eukaryotic DNA Mismatch Repair Reveals Distinct Recognition and Repair Associated Intermediates. Cell, 147(5), 1040–1053.
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