Area 4: DNA Helicases Involved in Maintenance of Genome Stability
The current projects within the laboratory focus on four critical areas:
The laboratory uses a combination of molecular, cellular, genetic, genome, and proteome approaches to study the function of many yeast and human membrane proteins as well as proteins involved in the maintenance of genome stability in humans.
The maintenance of the genetic material (so called “genome stability”) is an essential process in every living organism, and the failure of this process can lead to the development and progression of cancer. If we are to understand the causes of genome instability in humans, we must first understand the function of proteins that normally act to keep the genetic material intact. We study one such family of proteins called RecQ helicases using human cells as a model to characterize their roles in preserving the genome stability and onset of cancer.
The mutations in three different human RecQ helicase family members called BLM, WRN and RECQL4 lead to five human disorders characterized by genome instability and cancer predisposition. Werner syndrome (WS), linked to a defect in the WRN protein, is characterized by the appearance of unusually accelerated aging (progeria). Bloom syndrome (BS), which is associated with a defect in the BLM protein, is characterized by stunted growth, developmental problems, immunodeficiency, male infertility and, at the cellular level, a slowing of S-phase progression and a dramatic increase in sister chromatid exchange and genomic instability . Interestingly, three different human disorders have been associated with mutations in the RECQL4 gene: Rothmund-Thompson, RAPADILINO, and Baller-Gerold syndromes. Previously, our laboratory has identified several proteins that modulate the function of BLM, WRN and RECQL4 and thus contributed to understanding the causes of increased cancer rates in these patients.
Despite much research, it is still not clear what role RecQ helicases play in the cell and why cells lacking these proteins show genome instability. We are applying a combination of molecular-biological, cellular and biochemical approaches to decipher the role of the BLM, RECQL4 and WRN in the onset of the above-mentioned cancer predisposition syndromes in humans. Although these cancer susceptibility syndromes are rare, we envisage that our data will give insight into how faulty RecQ helicases hinder the normal process of DNA repair, replication and recombination, and how defects in this process can increase the risk of cancer. Lastly, our studies will be relevant to childhood cancer since information obtained from our results may potentially allow a considerable extension of life in patients suffering from these cancer susceptibility syndromes.
Dietschy, T., Shevelev, I., Mak, R., Fahad Miah, M., Hess, D., Fey, M., Janscak, P., Hottiger, M., and Stagljar, I. (2009) p300-mediated acetylation of the Rothmund-Thomson-syndrome gene product RECQL4 regulates its subcellular localization, J Cell Sci 122, 1258-1267.
Selak, N., Bachrati, C.Z., Shevelev, I., Dietschy, T., Jacob, A., Hübscher, U., Hoheisel, J.D., Hickson, I.D., and Stagljar, I. (2008)
The Bloom’s syndrome helicase (BLM) interacts physically and functionally with p12, the smallest subunit of human DNA polymerase δ, Nucleic Acids Res 36, 5166-5179.
Jiao, R., Harrigan, J.A., Selak, N., Dietchy, T., Shevelev, I., Piotrowski, J., Indig, F.D., Bohr, V.A., and Stagljar, I. (2007)
The Werner syndrome protein is required for recruitment of chromatin assembly factor 1 following DNA damage,
Oncogene 6, 3811-3822.
Dietschy, T., Shevelev, I., and Stagljar, I. (2007)
The molecular role of the Rothmund-Thomson, RAPADILINO and Gerhard-Bäller gene product, RECQL4: a recent progress, Cell Mol Life Sci 64, 796-802.
Saydam, N., Garcia, P., Dietschy, T., Shevelev, I., Stagljar, I., and Janscak, P. (2007) DNA damage-specific association of the Werner syndrome helicase with the mismatch-repair proteins, Nucl Acids Res 35, 5706-5716.
Petkovic, M., Dietschy, T., Freire, R., Jiao, R., and Stagljar, I. (2005) The Rothmund-Thomson's syndrome gene product, RECQL4, localizes to defined nuclear foci and co-localizes with proteins involved in the maintanance of genome stability, J Cell Sci 118 , 4261-4269.
Jiao, R., Bachrati, C., Pedrazzi, G., Kuster, P., Petkovic, M., Li, J-L., Egli, D., Hickson, I.D., and Stagljar, I. (2004) Physical and functional interaction between the Bloom's syndrome gene product and CAF-1 hp150, the largest subunit of chromatin assembly factor 1, Mol Cell Biol 24, 4710-4719.