Alison Bertuch, M.D., Ph.D.
Associate Professor, Departments of Pediatrics and Molecular & Human Genetics
M.D., Ph.D., University of Rochester
Postdoctoral Training, Pediatric Residency, Pediatric Fellowship, Baylor College of Medicine
The Bertuch laboratory is interested in the mechanisms by which cells differentiate natural chromosome termini from DNA ends created by double-strand breaks (DSBs). DSBs present a significant threat to genome integrity because of the permanent cell cycle arrest or cell death they induce if left unrepaired. Consequently, organisms have evolved complex mechanisms to efficiently respond to and repair chromosomal DSBs. Natural chromosome termini, on the other hand, must be protected at least to some extent from these same pathways in order to prevent the fusion of chromosome ends or other detrimental outcomes. This is achieved through the specialized nucleoprotein structures known as telomeres. Paradoxically, many activities that function in the response to DSBs also have roles in normal telomere structure, function, and maintenance.
The Ku heterodimer is one such protein with dual roles at broken and telomeric ends. Ku is a high affinity DNA end binding complex critical for DNA DSB repair via nonhomologous end joining (NHEJ) and, surprisingly, multiple aspects of telomere biology. Previous work by us and others has firmly established that Ku performs separable activities at DSBs versus telomeres, however the mechanisms of action at these sites have yet to be fully elucidated. Ku is also a principal mediator of the catastrophic end-to-end fusions that can occur at dysfunctional telomeres. How Ku’s NHEJ activity is inhibited at wild type telomeres remains poorly defined. We are pursuing the answers to these questions in Saccharomyces cerevisiae, a genetically tractable model organism, which has contributed greatly to our current understanding of telomere biology and DNA DSB repair. Most recently, as a result of a comprehensive site-directed mutagenesis of the yeast Ku70 and Ku80 subunit genes, we have proposed a ‘two-face’ model for Ku’s functions at DSBs versus telomeres - whereby there is an outward face that mediates NHEJ and an inward face that mediates Ku’s telomeric functions. Our current work seeks to test and expand various aspects of this model and to elucidate the molecular determinants of Ku’s ability to protect telomeric ends from aberrant repair activities.
In addition, the lab is studying the mechanisms of telomere dysfunction in the bone marrow failure- and cancer-predisposition syndrome, dyskeratosis congenita (DC). DC. The underlying cellular pathology in DC is a defect in telomere maintenance. In many cases, the defect arises from mutations in genes encoding components of telomerase, the telomere replication enzyme, or proteins that are required for normal telomerase biogenesis or stability. Mutations in these genes results in decreased telomerase activity and resultant telomere shortening. Recently, TINF2, which encodes TIN2, was found mutated in DC, becoming the second most commonly mutated gene identified in the disorder. We are studying how DC-associated TINF2 mutations result in telomere function and the genetic basis of telomere dysfunction in patients with DC who appear to lack mutations in the six known DC-associated genes.
Liti, G., Haricharan, S., Cubillos, F., Tierney, A.L., Sharp, S., Bertuch, A.A., Parts, L., Bailes, E. and Louis, E.J. 2009. Segregating Ku80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast. PLoS Genetics 5(9):e1000659.
Indiviglio, S. and Bertuch, A.A. 2009. Ku’s essential role in keeping telomeres intact. Proc. Natl. Acad. Sci. USA. 106:12217-12218. PMID: 19622731
Marvin, M.E., Becker, M.M., Noel, P., Hardy, S., Bertuch, A.A. and Louis, E.J. 2009. The association of yeast Ku with subtelomeric Core X sequences is independent of silencing. Genetics. Epub before print. PMID: 19652176.
Horton, T.M., Jenkins, G., Pati, D., Zhang, L., Dolan, E.M., Ribes-Zamora, A., Blaney, S.M., Hegde, M., Bertuch, A.A., and Berg, S.L. 2009. PARP Inhibitor ABT-888 potentiates the antitumor activity of temozolomide in leukemia cells: influence of mismatch repair status and MGMT activity. Mol. Cancer Thera. 8:2232-2242. PMID: 19671751
Muscal JA, Jones JY, Paulino AC, Bertuch AA, Su J, Woo SY, Mahoney DH Jr, Chintagumpala M. 2008. Changes Mimicking New Leptomeningeal Disease After Intensity-Modulated Radiotherapy for Medulloblastoma. Int J Radiat Oncol Biol Phys. 73:214-221. PMID: 18485616
Louis CU, Paulino AC, Gottschalk S, Bertuch AA, Chintagumpala M, Heslop HE, Russell HV. 2007. A single institution experience with pediatric nasopharyngeal carcinoma: high incidence of toxicity associated with platinum-based chemotherapy plus IMRT. J Pediatr Hematol Oncol. 20:500-505. PMID: 17609631
Ribes-Zamora, A., Mihalek, I., Lichtarge, O. and Bertuch, A.A. 2007. Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions. Nature Struct. Mol. Biol. 14:301-307.
Bertuch, A.A. and Lundblad, V. 2006. The maintenance and masking of chromosome termini. Curr. Opin. Cell Biol. 18:247-253.
Hermanns, P., Bertuch, A.A., Bertin, T., Dawson, B., Schmitt, M.E., Zabel, B., and Lee, B. 2005. Consequences of mutations in the noncoding RMRP RNA in the pathogenesis of Cartilage-Hair Hypoplasia. Human Mol. Genetics 14:3723-3740.
Bertuch, A.A. and Lundblad, V. 2004. EXO1 contributes to telomere maintenance in both telomerase-proficient and telomerase-deficient Saccharomyces cerevisiae. Genetics 166: 1651-1659.
Bertuch, A.A. and Lundblad, V. 2003. The Ku heterodimer performs separable activities at double strand breaks and chromosome termini. Mol. Cell. Biol. 23:8202-8215.
Bertuch, A.A., Buckley, K., and Lundblad, V. 2003. The way to the end matters: the role of telomerase in tumor progression. Cell Cycle 2:36-38.
Bertuch, A.A. and Lundblad, V. 2003. Which end: dissecting Ku's function at telomeres and double-strand breaks. Genes Dev. 17:2347-2350.
Bertuch, A.A. 2002. When ends meet: The molecular events driving telomeric fusions. Curr. Biol. 12:R738-40.
Evans, S.K., Bertuch, A.A. and Lundblad, V. 1999. Telomeres and telomerase: at the end it all comes together. Trends Cell Biol. 9:329-331.
Bertuch, A. and Lundblad, V. 1998. Telomeres and double-strand breaks: trying and to make end meet. Trends Cell Biol. 8:339-342.
For more publications, see listing on PubMed.
Alison Bertuch, M.D., Ph.D.
Department of Pediatrics
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
Telephone: (832) 824-4579