Positions

Associate Professor
Pediatrics-Oncology
Baylor College of Medicine
Houston, TX, US
Associate Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas, United States
Co-Director
Graduate Program in Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas, United States
Associate Professor
Program in Integrative Molecular and Biomedical Sciences
Baylor College of Medicine
Houston, Texas, United States
Assistant Dean for Curriculum
Graduate School of Biomedical Sciences
Baylor College of Medicine
Houston, Texas, United States
Member
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States

Education

BS from Massachusetts Institute Of Technology
MD from University Of Rochester School Of Medicine And Dentistry
PhD from University Of Rochester
Internship at Baylor College Of Medicine Affiliate Hospitals
Pediatrics
Residency at Baylor College Of Medicine Affiliate Hospitals
Pediatrics
Clinical Fellowship at Baylor College of Medicine
Pediatric Hematology/Oncology
Postdoctoral Training at Baylor College of Medicine

Professional Interests

  • Basic mechanisms of telomere maintenance, structure, and function and DNA repair in the yeast model organism and human cells
  • Molecular genetics of dyskeratosis congenita and other inherited bone marrow failure syndromes

Professional Statement

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