Biomedical Research Education & Training
Faculty Member

Cortez, David, Ph.D.
Professor of Biochemistry
Ingram Professor of Cancer Research
Professor of Cancer Biology

Lab Url:

Phone Number: 615-322-8547

Email Address:

Cortez, David's picture
Academic history
B.S., Univ of Illinois, Champaign-Urbana
B.S., Univ of Illinois, Champaign-Urbana
Ph.D., Duke University

Office Address   Mailing Address

613 LIght Hall

613B Light Hall 0146

Research Keywords
cell cycle, DNA damage, replication, proteolysis, signaling, DNA repair, checkpoint, ,Biochemistry,Cancer,Cell cycle,Chromosome,DNA repair,DNA synthesis,Genetics,Genome,Kinase,Mass spectroscopy,Mutation,Phosphorylation,Post-transcriptional modification,Proteomics,Recombination,Signal transduction,Toxicology,Transformation,Yeast

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.

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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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

B??tous, R, Glick, GG, Zhao, R, Cortez, D. Identification and Characterization of SMARCAL1 Protein Complexes. PLoS One, 8(5), e63149, 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

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

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

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

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

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

Bansbach, CE, Cortez, D. Defining genome maintenance pathways using functional genomic approaches. Crit Rev Biochem Mol Biol, 46(4), 327-41, 2011

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

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

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, Boerkoel, CF, Cortez, D. SMARCAL1 and replication stress: An explanation for SIOD. Nucleus, 1(3), 245-248, 2010 PMCID:3027029

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

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 PMCID:3027029

Bansbach, CE, B??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

Lovejoy, CA, Cortez, D. Common mechanisms of PIKK regulation. DNA Repair (Amst), 8, 1004-8, 2009 PMCID:2725225

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

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 PMCID:2373760

Cimprich, KA, Cortez, D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol, 9(8), 616-27, 2008 PMCID:2663384

Mordes, DA, Cortez, D. Activation of ATR and related PIKKs. Cell Cycle, 7(18), 2809-12, 2008 PMCID:2672405

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 PMCID:2418584

Mordes, DA, Nam, EA, Cortez, D. Dpb11 activates the Mec1-Ddc2 complex. Proc Natl Acad Sci U S A, 105(48), 18730-4, 2008 PMCID:2596233

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 PMCID:2593429

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 PMCID:1899971

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 PMCID:1855264

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 PMCID:2728292

Lovejoy, CA, Lock, K, Yenamandra, A, Cortez, D. DDB1 maintains genome integrity through regulation of Cdt1. Mol Cell Biol, 26, 7977-7990, 2006 PMCID:1636754

Myers J.S., Cortez D. Rapid Activation of ATR by Ionizing Radiation Requires ATM and Mre11. J Biol Chem, 281(14), 9346-50, 2006 PMCID:1821075

Ball H.L., Cortez D. ATRIP oligomerization is required for ATR-dependent checkpoint signaling. J Biol Chem, 280(36), 31390-6, 2005 PMCID:1360181

Ball, HL, Myers, JS, Cortez, D. ATRIP Binding to RPA-ssDNA Promotes ATR-ATRIP Localization but Is Dispensable for Chk1 Phosphorylation. Mol Biol Cell, 16, 2372-2381, 2005 PMCID:1087242

Cortez, D. Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling. Genes Dev, 19(9), 1007-12, 2005 PMCID:1360198

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 PMCID:454167

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 PMCID:155323

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, 98, 6086-91, 2001

Cortez D, Elledge SJ. Conducting the mitotic symphony. Nature, 406, 354-6, 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 PMCID:316686

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, 14, 2989-3002, 2000

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 PMCID:316544

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

Postdoctoral Position Available

Postdoctoral Position 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.

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