David K. Cortez, Ph.D.
Ingram Professor of Cancer Research
Professor of Biochemistry
Vanderbilt University Medical Center
613 Light Hall
Nashville, TN 37232-0146
Genome maintenance by the DNA damage response
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.
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.
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- Couch, FB, Bansbach, CE, Driscoll, R, Luzwick, JW, Glick, GG, B¿¿tous, R, Carroll, CM, Jung, SY, Qin, J, Cimprich, KA, Cortez, D ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev, 27(14), 1610-23, 2013.
- Sirbu, BM, Cortez, D DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol, 5(8), 2013.
- Summers, AR, Fischer, MA, Stengel, KR, Zhao, Y, Kaiser, JF, Wells, CE, Hunt, A, Bhaskara, S, Luzwick, JW, Sampathi, S, Chen, X, Thompson, MA, Cortez, D, Hiebert, SW HDAC3 is essential for DNA replication in hematopoietic progenitor cells. J Clin Invest, 123(7), 3112-23, 2013.
- B¿¿tous, R, Glick, GG, Zhao, R, Cortez, D Identification and Characterization of SMARCAL1 Protein Complexes. PLoS One, 8(5), e63149, 2013.
- Wells, CE, Bhaskara, S, Stengel, KR, Zhao, Y, Sirbu, B, Chagot, B, Cortez, D, Khabele, D, Chazin, WJ, Cooper, A, Jacques, V, Rusche, J, Eischen, CM, McGirt, LY, Hiebert, SW Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS One, 8(7), e68915, 2013.
- Carroll, C, Bansbach, CE, Zhao, R, Jung, SY, Qin, J, Cortez, D Phosphorylation of a C-terminal auto-inhibitory domain increases SMARCAL1 activity. Nucleic Acids Res, 2013.
- Carroll, C, Badu-Nkansah, A, Hunley, T, Baradaran-Heravi, A, Cortez, D, Frangoul, H Schimke immunoosseous dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. Pediatr Blood Cancer, 0, 2013.
- B¿¿tous, R, Couch, FB, Mason, AC, Eichman, BF, Manosas, M, Cortez, D Substrate-selective repair and restart of replication forks by DNA translocases. Cell Rep, 3(6), 1958-69, 2013.
- Sirbu, BM, Couch, FB, Cortez, D Monitoring the spatiotemporal dynamics of proteins at replication forks and in assembled chromatin using isolation of proteins on nascent DNA. Nat Protoc, 7(3), 594-605, 2012.
- B¿¿tous, R, Mason, AC, Rambo, RP, Bansbach, CE, Badu-Nkansah, A, Sirbu, BM, Eichman, BF, Cortez, D SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes Dev, 26(2), 151-62, 2012.
- Nam, EA, Cortez, D ATR signalling: more than meeting at the fork. Biochem J, 436(3), 527-36, 2011.
- Nam, EA, Zhao, R, Cortez, D Analysis of mutations that dissociate G(2) and essential S phase functions of human ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase. J Biol Chem, 286(43), 37320-7, 2011.
- Sirbu, BM, Couch, FB, Feigerle, JT, Bhaskara, S, Hiebert, SW, Cortez, D Analysis of protein dynamics at active, stalled, and collapsed replication forks. Genes Dev, 25(12), 1320-7, 2011.
- Bansbach, CE, Cortez, D Defining genome maintenance pathways using functional genomic approaches. Crit Rev Biochem Mol Biol, 46(4), 327-41, 2011.
- Nam, EA, Zhao, R, Glick, GG, Bansbach, CE, Friedman, DB, Cortez, D T1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and rad3-related (ATR) kinase. J Biol Chem, 2011.
- Yu, DS, Zhao, R, Hsu, EL, Cayer, J, Ye, F, Guo, Y, Shyr, Y, Cortez, D Cyclin-dependent kinase 9-cyclin K functions in the replication stress response. EMBO Rep, 11(11), 876-82, 2010.
- Bansbach, CE, Boerkoel, CF, Cortez, D SMARCAL1 and replication stress: An explanation for SIOD. Nucleus, 1(3), 245-248, 2010.
- Wiltshire, TD, Lovejoy, CA, Wang, T, Xia, F, O''Connor, MJ, Cortez, D Sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol Chem, 2010.
- Lovejoy, CA, Cortez, D Common mechanisms of PIKK regulation. DNA Repair (Amst), 81004-8, 2009.
- Lovejoy, CA, Xu, X, Bansbach, CE, Glick, GG, Zhao, R, Ye, F, Sirbu, BM, Titus, LC, Shyr, Y, Cortez, D Functional genomic screens identify CINP as a genome maintenance protein. Proc Natl Acad Sci U S A, 2009.
- Nam, EA, Cortez, D SOSS1/2: Sensors of single-stranded DNA at a break. Mol Cell, 35(3), 258-9, 2009.
- Bansbach, CE, BÃ©tous, R, Lovejoy, CA, Glick, GG, Cortez, D The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev, 23(20), 2405-14, 2009.
- Cimprich, KA, Cortez, D ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol, 9(8), 616-27, 2008.
- Mordes, DA, Cortez, D Activation of ATR and related PIKKs. Cell Cycle, 7(18), 2809-12, 2008.
- Bhaskara, S, Chyla, BJ, Amann, JM, Knutson, SK, Cortez, D, Sun, ZW, Hiebert, SW Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell, 30(1), 61-72, 2008.
- Mordes, DA, Nam, EA, Cortez, D Dpb11 activates the Mec1-Ddc2 complex. Proc Natl Acad Sci U S A, 105(48), 18730-4, 2008.
- Xu, X, Vaithiyalingam, S, Glick, GG, Mordes, DA, Chazin, WJ, Cortez, D The basic cleft of RPA70N binds multiple checkpoint proteins including RAD9 to regulate ATR signaling. Mol Cell Biol, 2008.
- Mordes, DA, Glick, GG, Zhao, R, Cortez, D TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev, 22(11), 1478-89, 2008.
- Myers, JS, Zhao, R, Xu, X, Ham, AJ, Cortez, D Cyclin-dependent kinase 2 dependent phosphorylation of ATRIP regulates the G2-M checkpoint response to DNA damage. Cancer Res, 67(14), 6685-90, 2007.
- Ball, HL, Ehrhardt, MR, Mordes, DA, Glick, GG, Chazin, WJ, Cortez, D Function of a Conserved Checkpoint Recruitment Domain in ATRIP Proteins. Mol Cell Biol, 27(9), 3367-77, 2007.
- Chen, X, Zhao, R, Glick, GG, Cortez, D Function of the ATR N-terminal domain revealed by an ATM/ATR chimera. Exp Cell Res, 313(8), 1667-74, 2007.
- Lovejoy, CA, Lock, K, Yenamandra, A, Cortez, D DDB1 maintains genome integrity through regulation of Cdt1. Mol Cell Biol, 267977-7990, 2006.
- Myers J.S., Cortez D Rapid Activation of ATR by Ionizing Radiation Requires ATM and Mre11. J Biol Chem, 281(14), 9346-50, 2006.
- Ball, HL, Myers, JS, Cortez, D ATRIP Binding to RPA-ssDNA Promotes ATR-ATRIP Localization but Is Dispensable for Chk1 Phosphorylation. Mol Biol Cell, 162372-2381, 2005.
- Ball H.L., Cortez D ATRIP oligomerization is required for ATR-dependent checkpoint signaling. J Biol Chem, 280(36), 31390-6, 2005.
- Cortez, D Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling. Genes Dev, 19(9), 1007-12, 2005.
- Cortez D., Glick G., Elledge S.J Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc Natl Acad Sci U S A, 101(27), 10078-83, 2004.
- Cortez, David Caffeine inhibits checkpoint responses without inhibiting ATM and ATR. J Biol Chem, 278(39), 37139-45, 2003.
- Zou, L, Cortez, D, Elledge, SJ Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev, 16(2), 198-208, 2002.
- Cortez, D, Guntuku, S, Qin, J, Elledge, SJ ATR and ATRIP: partners in checkpoint signaling. Science, 294(5547), 1713-6, 2001.
- Paull T.T., Cortez D., Bowers B., Elledge S.J., Gellert M "Direct DNA binding by Brca1." Proc. Natl. Acad. Sci. USA, 986086-91, 2001.
- Wang, Y, Cortez, D, Yazdi, P, Neff, N, Elledge, SJ, Qin, J BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev, 14(8), 927-39, 2000.
- Liu, Q, Guntuku, S, Cui, XS, Matsuoka, S, Cortez, D, Tamai, K, Luo, G, Carattini-Rivera, S, DeMayo, F, Bradley, A, Donehower, LA, Elledge, SJ Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev, 14(12), 1448-59, 2000.
- Cortez D, Elledge SJ "Conducting the mitotic symphony." Nature, 406354-6, 2000.
- Tibbetts, R.S., Cortez, D., Brumbaugh, K.M., Scully, R., Livingston, D., Elledge, S.J., Abraham, R.T "Functional interactions betweeen BRCA1 and the checkpoint kinase ATR during genotoxic stress." Genes and Development, 142989-3002, 2000.
- Cortez, D, Wang, Y, Qin, J, Elledge, SJ Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science, 286(5442), 1162-6, 1999.