Name: Cortez, David
Title: Professor of Biochemistry
Office Address: 613B Light Hall
Phone Number: 615-322-8547
Lab URL: http://www.mc.vanderbilt.edu/root/vumc.php?site=cortezlab
Research Keywords: cell cycle, DNA damage, replication, proteolysis, signaling, DNA repair, checkpoint,
Research Specialty: Genome maintenance by the DNA damage response
Research Description: My laboratory is dedicated to discovering the basic biological processes that govern cell growth and genome stability. Cancer arises as a result of genetic alterations. Cells deploy numerous genome surveillance systems to prevent and repair DNA damage and to coordinate repair with cell cycle transitions. However, cancer cells have lost some of these systems and are genetically unstable. We aim to define the components of genomic surveillance systems and understand how they work in a coordinated manner to prevent cancer by inhibiting the cell cycle, promoting DNA repair, or initiating apoptosis. The DNA damage response pathway is a signal transduction pathway that functions within the cell nucleus. Proteins involved in these pathways include ATM, ATR, p53, Chk2, Brca1, FancD2, and Blms. Mutations in the genes encoding these proteins are linked to specific cancer predisposition, developmental, and premature aging syndromes.
Our primary research goal is to understand how DNA damage response pathways function to maintain genome integrity and prevent cancer. There are currently four specific focuses in the laboratory: 1) Activation mechanisms of the DNA damage response and checkpoint kinases ATM and ATR. 2) Regulation of DNA replication to ensure genome stability. 3) The use of RNAi for genetic screens to identify genome maintenance genes. 4) Analysis of DNA damage responses in cancer and opportunities for therapeutic intervention. We use a variety of genetic and biochemical approaches in mammalian and yeast systems. RNA inhibition, gene knockouts, cell biology, mass spectrometry, and yeast genetics all are employed as needed to understand the basic molecular mechanisms that maintain our genomes.
We also collaborate with structural biologists to gain a more detailed understanding of how protein-protein interactions regulate DNA damage responses. An exciting new area of investigation involves the use of genetic screens in human cells to understand genome maintenance. We believe that our multidisciplinary approach to studying these topics will yield new insights into the molecular basis of cancer and aging. SIGNIFICANCE The cancer predisposition syndrome ataxia telangiectasia (A-T) illustrates the physiological importance of genetic surveillance pathways. Individuals carrying two mutant ATM (A-T mutated) genes suffer loss of fine motor control, immune deficiencies, and high frequencies of cancer. Furthemore, heterozygous carriers of ATM mutations (1% of the population) are at an increased risk of breast cancer. ATM is a central signaling protein in the DNA damage response, and cells lacking ATM fail to execute many of the cellular responses to DNA damage. Since DNA damage is continuously produced as a byproduct of normal cell metabolism and DNA replication, any deficiency in responding to and repairing this damage can cause chromosomal alterations that may lead to cancer. In addition many cancer therapies including radiation therapy and most chemotherapeutic strategies cause DNA damage. Therefore, manipulating the DNA damage response may be one means of improving the outcomes of these therapies.
Postdoctoral Position Availability and Details: Postdoctoral positions are available in the areas of molecular cancer biology, signal transduction, cell cycle, and DNA repair. Please submit a CV and three letters of recommendation.