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Molecular and Human Genetics

Houston, Texas

Department of Molecular and Human Genetics
Department of Molecular and Human Genetics
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Alison A. Bertuch, M.D., Ph.D.

Alison A. Bertuch, M.D., Ph.D.

Associate Professor of Molecular and Human Genetics

Other Positions

Associate Professor, Department of Pediatrics - Hematology/Oncology; Program in Integrative Molecular and Biomedical Sciences
Co-Director, Graduate Program in Molecular and Human Genetics


B.S., Biology, Massachusetts Institute of Technology, 1981-1985
M.S., M.D., and Ph.D., Biology, University of Rochester, 1985-1993
Internship, Pediatrics, Baylor College of Medicine, 1993-1994
Residency, Pediatrics, Baylor College of Medicine, 1994-1996
Clinical Fellow, Pediatric Hematology/Oncology, Baylor College of Medicine, 1996-1999
Postdoc, Baylor College of Medicine, 1997-2003

Research Interests

My 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. Through 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 repair activities. Most recently, we have translated our work on Ku in yeast to human cells, proposing an additional mechanism by which human telomeres are prevented from being engaged in NHEJ.

In addition, my laboratory studies the mechanisms of telomere dysfunction in the bone marrow failure- and cancer-predisposition syndrome, dyskeratosis congenita (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 over generations. TINF2 is the second most commonly mutated gene identified in the disorder and encodes a protein that binds to telomeres. Mutations in TINF2 most often result in dramatically short telomeres in a single generation by an unknown mechansim. My laboratory is studying how TINF2 mutations impact telomeres and the genetic basis of telomere dysfunction in patients with DC who appear to lack mutations in the known DC-associated genes.

Selected Publications

  1. Ribes-Zamora A*, Indiviglio S*, Mihalek I, Williams CL, Bertuch AA (2013). TRF2 interaction with Ku heterotetramerization interface gives insight into prevention of c-NHEJ at human telomeres. *Co-first authors. Cell Rep. doi: 10.1016/j.celrep.2013.08.040. [Epub ahead of print] PMID: 24095731
  2. Gramatges MM, Bertuch AA (2013). Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy. Transl. Res., in press. PubMed PMID: 23732052
  3. Gramatges MM, Qi X, Sasa GS, Chen JJ, Bertuch AA (2013). A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. Blood 121(18): 3586-93. PubMed PMID: 23538340
  4. Sasa G, Ribes-Zamora A, Nelson N, Bertuch A (2012). Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clin. Genet. 81(5): 470-8. PubMed PMID: 21477109
  5. Nelson ND, Bertuch AA (2012). Dyskeratosis congenita as a disorder of telomere maintenance. Mutat. Res. 730(1-2): 43-51. PubMed PMID: 21745483
  6. Canudas S, Houghtaling BR, Bhanot M, Sasa G, Savage SA, Bertuch AA, Smith S (2011). A role for heterochromatin protein 1{gamma} at human telomeres. Genes Dev. 25(17): 1807-19. PubMed PMID: 21865325
  7. Lopez CR, Ribes-Zamora A, Indiviglio SM, Williams CL, Haricharan S, Bertuch AA (2011). Ku Must Load Directly onto the Chromosome End in Order to Mediate Its Telomeric Functions. PLoS Genet. 7(8): e1002233. PubMed PMID: 21852961
  8. Olofsson P, Bertuch AA (2010). Modeling growth and telomere dynamics in Saccharomyces cerevisiae. J. Theor. Biol. 263(3): 353-9. PubMed PMID: 20018194
  9. Indiviglio SM, Bertuch AA (2009). Ku's essential role in keeping telomeres intact. Proc. Natl. Acad. Sci. U S A 106(30): 12217-8. PubMed PMID: 19622731
  10. Ribes-Zamora A, Mihalek I, Lichtarge O, Bertuch AA (2007). Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions. Nat. Struct. Mol. Biol. 14(4): 301-7. PubMed PMID: 17351632

Contact Information

Alison A. Bertuch, M.D., Ph.D.
Department of Pediatrics - Hematology/Oncology
Baylor College of Medicine
One Baylor Plaza, MS BCM320
Houston, TX, 77030, U.S.A.

Phone: 832-824-4579
Fax: 832-825-4202

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