David Cortez
Faculty Member
Last active: 2/4/2016

Profile

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.


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Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. SMARCAL1 maintains telomere integrity during DNA replication. Poole LA, Zhao R, Glick GG, Lovejoy CA, Eischen CM, Cortez D (2015) Proc Natl Acad Sci U S A 112(48): 14864-9
    › Primary publication · 26578802 (PubMed) · PMC4672769 (PubMed Central)
  2. Stephen Elledge and the DNA damage response. Cortez D, Zhou Z, Sanchez Y (2015) DNA Repair (Amst) : 156-7
    › Primary publication · 26574138 (PubMed)
  3. A whole genome RNAi screen identifies replication stress response genes. Kavanaugh G, Ye F, Mohni KN, Luzwick JW, Glick G, Cortez D (2015) DNA Repair (Amst) : 55-62
    › Primary publication · 26454783 (PubMed) · PMC4651756 (PubMed Central)
  4. The Replication Checkpoint Prevents Two Types of Fork Collapse without Regulating Replisome Stability. Dungrawala H, Rose KL, Bhat KP, Mohni KN, Glick GG, Couch FB, Cortez D (2015) Mol Cell 59(6): 998-1010
    › Primary publication · 26365379 (PubMed) · PMC4575883 (PubMed Central)
  5. Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing. Kavanaugh G, Zhao R, Guo Y, Mohni KN, Glick G, Lacy ME, Hutson MS, Ascano M, Cortez D (2015) Mol Cell Biol 35(17): 2979-90
    › Primary publication · 26100022 (PubMed) · PMC4525316 (PubMed Central)
  6. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments. Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D (2015) PLoS One 10(5): e0125482
    › Primary publication · 25965342 (PubMed) · PMC4428765 (PubMed Central)
  7. Preventing replication fork collapse to maintain genome integrity. Cortez D (2015) DNA Repair (Amst) : 149-157
    › Primary publication · 25957489 (PubMed) · PMC4522347 (PubMed Central)
  8. A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia. Carroll C, Hunley TE, Guo Y, Cortez D (2015) Am J Med Genet A 167A(10): 2260-4
    › Primary publication · 25943327 (PubMed) · PMC4743909 (PubMed Central)
  9. Simian virus Large T antigen interacts with the N-terminal domain of the 70 kD subunit of Replication Protein A in the same mode as multiple DNA damage response factors. Ning B, Feldkamp MD, Cortez D, Chazin WJ, Friedman KL, Fanning E (2015) PLoS One 10(2): e0116093
    › Primary publication · 25706313 (PubMed) · PMC4337903 (PubMed Central)
  10. High-affinity DNA-binding domains of replication protein A (RPA) direct SMARCAL1-dependent replication fork remodeling. Bhat KP, Bétous R, Cortez D (2015) J Biol Chem 290(7): 4110-7
    › Primary publication · 25552480 (PubMed) · PMC4326820 (PubMed Central)
  11. SV40 utilizes ATM kinase activity to prevent non-homologous end joining of broken viral DNA replication products. Sowd GA, Mody D, Eggold J, Cortez D, Friedman KL, Fanning E (2014) PLoS Pathog 10(12): e1004536
    › Primary publication · 25474690 (PubMed) · PMC4256475 (PubMed Central)
  12. Purification of proteins on newly synthesized DNA using iPOND. Dungrawala H, Cortez D (2015) Methods Mol Biol : 123-31
    › Primary publication · 25311126 (PubMed) · PMC4384176 (PubMed Central)
  13. Mutation of serine 1333 in the ATR HEAT repeats creates a hyperactive kinase. Luzwick JW, Nam EA, Zhao R, Cortez D (2014) PLoS One 9(6): e99397
    › Primary publication · 24901225 (PubMed) · PMC4047089 (PubMed Central)
  14. A structure-specific nucleic acid-binding domain conserved among DNA repair proteins. Mason AC, Rambo RP, Greer B, Pritchett M, Tainer JA, Cortez D, Eichman BF (2014) Proc Natl Acad Sci U S A 111(21): 7618-23
    › Primary publication · 24821763 (PubMed) · PMC4040553 (PubMed Central)
  15. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Mohni KN, Kavanaugh GM, Cortez D (2014) Cancer Res 74(10): 2835-45
    › Primary publication · 24662920 (PubMed) · PMC4043842 (PubMed Central)
  16. Fork reversal, too much of a good thing. Couch FB, Cortez D (2014) Cell Cycle 13(7): 1049-50
    › Primary publication · 24553113 (PubMed) · PMC4013150 (PubMed Central)
  17. Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A. Frank AO, Vangamudi B, Feldkamp MD, Souza-Fagundes EM, Luzwick JW, Cortez D, Olejniczak ET, Waterson AG, Rossanese OW, Chazin WJ, Fesik SW (2014) J Med Chem 57(6): 2455-61
    › Primary publication · 24491171 (PubMed) · PMC3969094 (PubMed Central)
  18. Phosphorylation of a C-terminal auto-inhibitory domain increases SMARCAL1 activity. Carroll C, Bansbach CE, Zhao R, Jung SY, Qin J, Cortez D (2014) Nucleic Acids Res 42(2): 918-25
    › Primary publication · 24150942 (PubMed) · PMC3902923 (PubMed Central)
  19. Identification of proteins at active, stalled, and collapsed replication forks using isolation of proteins on nascent DNA (iPOND) coupled with mass spectrometry. Sirbu BM, McDonald WH, Dungrawala H, Badu-Nkansah A, Kavanaugh GM, Chen Y, Tabb DL, Cortez D (2013) J Biol Chem 288(44): 31458-67
    › Primary publication · 24047897 (PubMed) · PMC3814742 (PubMed Central)
  20. HDAC3 is essential for DNA replication in hematopoietic progenitor cells. 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 (2013) J Clin Invest 123(7): 3112-23
    › Primary publication · 23921131 (PubMed) · PMC3696547 (PubMed Central)
  21. Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. 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 (2013) PLoS One 8(7): e68915
    › Primary publication · 23894374 (PubMed) · PMC3718806 (PubMed Central)
  22. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Bétous R, Carroll CM, Jung SY, Qin J, Cimprich KA, Cortez D (2013) Genes Dev 27(14): 1610-23
    › Primary publication · 23873943 (PubMed) · PMC3731549 (PubMed Central)
  23. DNA damage response: three levels of DNA repair regulation. Sirbu BM, Cortez D (2013) Cold Spring Harb Perspect Biol 5(8): a012724
    › Primary publication · 23813586 (PubMed) · PMC3721278 (PubMed Central)
  24. Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4. Nagarajan P, Ge Z, Sirbu B, Doughty C, Agudelo Garcia PA, Schlederer M, Annunziato AT, Cortez D, Kenner L, Parthun MR (2013) PLoS Genet 9(6): e1003518
    › Primary publication · 23754951 (PubMed) · PMC3675013 (PubMed Central)
  25. Substrate-selective repair and restart of replication forks by DNA translocases. Bétous R, Couch FB, Mason AC, Eichman BF, Manosas M, Cortez D (2013) Cell Rep 3(6): 1958-69
    › Primary publication · 23746452 (PubMed) · PMC3700663 (PubMed Central)
  26. Identification and characterization of SMARCAL1 protein complexes. Bétous R, Glick GG, Zhao R, Cortez D (2013) PLoS One 8(5): e63149
    › Primary publication · 23671665 (PubMed) · PMC3650004 (PubMed Central)
  27. Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. Carroll C, Badu-Nkansah A, Hunley T, Baradaran-Heravi A, Cortez D, Frangoul H (2013) Pediatr Blood Cancer 60(9): E88-90
    › Primary publication · 23630135 (PubMed) · PMC3713188 (PubMed Central)
  28. Monitoring the spatiotemporal dynamics of proteins at replication forks and in assembled chromatin using isolation of proteins on nascent DNA. Sirbu BM, Couch FB, Cortez D (2012) Nat Protoc 7(3): 594-605
    › Primary publication · 22383038 (PubMed) · PMC3671908 (PubMed Central)
  29. SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Bétous R, Mason AC, Rambo RP, Bansbach CE, Badu-Nkansah A, Sirbu BM, Eichman BF, Cortez D (2012) Genes Dev 26(2): 151-62
    › Primary publication · 22279047 (PubMed) · PMC3273839 (PubMed Central)
  30. Analysis of mutations that dissociate G(2) and essential S phase functions of human ataxia telangiectasia-mutated and Rad3-related (ATR) protein kinase. Nam EA, Zhao R, Cortez D (2011) J Biol Chem 286(43): 37320-7
    › Primary publication · 21908846 (PubMed) · PMC3199479 (PubMed Central)
  31. Defining genome maintenance pathways using functional genomic approaches. Bansbach CE, Cortez D (2011) Crit Rev Biochem Mol Biol 46(4): 327-41
    › Primary publication · 21787120 (PubMed) · PMC3144553 (PubMed Central)
  32. Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. Nam EA, Zhao R, Glick GG, Bansbach CE, Friedman DB, Cortez D (2011) J Biol Chem 286(33): 28707-14
    › Primary publication · 21705319 (PubMed) · PMC3190678 (PubMed Central)
  33. Analysis of protein dynamics at active, stalled, and collapsed replication forks. Sirbu BM, Couch FB, Feigerle JT, Bhaskara S, Hiebert SW, Cortez D (2011) Genes Dev 25(12): 1320-7
    › Primary publication · 21685366 (PubMed) · PMC3127432 (PubMed Central)
  34. ATR signalling: more than meeting at the fork. Nam EA, Cortez D (2011) Biochem J 436(3): 527-36
    › Primary publication · 21615334 (PubMed) · PMC3678388 (PubMed Central)
  35. SMARCAL1 and replication stress: an explanation for SIOD? Bansbach CE, Boerkoel CF, Cortez D (2010) Nucleus 1(3): 245-8
    › Primary publication · 21327070 (PubMed) · PMC3027029 (PubMed Central)
  36. Cyclin-dependent kinase 9-cyclin K functions in the replication stress response. Yu DS, Zhao R, Hsu EL, Cayer J, Ye F, Guo Y, Shyr Y, Cortez D (2010) EMBO Rep 11(11): 876-82
    › Primary publication · 20930849 (PubMed) · PMC2966956 (PubMed Central)
  37. ATR and ATRIP are recruited to herpes simplex virus type 1 replication compartments even though ATR signaling is disabled. Mohni KN, Livingston CM, Cortez D, Weller SK (2010) J Virol 84(23): 12152-64
    › Primary publication · 20861269 (PubMed) · PMC2976399 (PubMed Central)
  38. Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. Wiltshire TD, Lovejoy CA, Wang T, Xia F, O'Connor MJ, Cortez D (2010) J Biol Chem 285(19): 14565-71
    › Primary publication · 20233726 (PubMed) · PMC2863164 (PubMed Central)
  39. Functional genomic screens identify CINP as a genome maintenance protein. Lovejoy CA, Xu X, Bansbach CE, Glick GG, Zhao R, Ye F, Sirbu BM, Titus LC, Shyr Y, Cortez D (2009) Proc Natl Acad Sci U S A 106(46): 19304-9
    › Primary publication · 19889979 (PubMed) · PMC2780779 (PubMed Central)
  40. The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Bansbach CE, Bétous R, Lovejoy CA, Glick GG, Cortez D (2009) Genes Dev 23(20): 2405-14
    › Primary publication · 19793861 (PubMed) · PMC2764496 (PubMed Central)
  41. SOSS1/2: Sensors of single-stranded DNA at a break. Nam EA, Cortez D (2009) Mol Cell 35(3): 258-9
    › Primary publication · 19683490 (PubMed) · PMC2820400 (PubMed Central)
  42. Common mechanisms of PIKK regulation. Lovejoy CA, Cortez D (2009) DNA Repair (Amst) 8(9): 1004-8
    › Primary publication · 19464237 (PubMed) · PMC2725225 (PubMed Central)
  43. Dpb11 activates the Mec1-Ddc2 complex. Mordes DA, Nam EA, Cortez D (2008) Proc Natl Acad Sci U S A 105(48): 18730-4
    › Primary publication · 19028869 (PubMed) · PMC2596233 (PubMed Central)
  44. The basic cleft of RPA70N binds multiple checkpoint proteins, including RAD9, to regulate ATR signaling. Xu X, Vaithiyalingam S, Glick GG, Mordes DA, Chazin WJ, Cortez D (2008) Mol Cell Biol 28(24): 7345-53
    › Primary publication · 18936170 (PubMed) · PMC2593429 (PubMed Central)
  45. Activation of ATR and related PIKKs. Mordes DA, Cortez D (2008) Cell Cycle 7(18): 2809-12
    › Primary publication · 18769153 (PubMed) · PMC2672405 (PubMed Central)
  46. ATR: an essential regulator of genome integrity. Cimprich KA, Cortez D (2008) Nat Rev Mol Cell Biol 9(8): 616-27
    › Primary publication · 18594563 (PubMed) · PMC2663384 (PubMed Central)
  47. TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Mordes DA, Glick GG, Zhao R, Cortez D (2008) Genes Dev 22(11): 1478-89
    › Primary publication · 18519640 (PubMed) · PMC2418584 (PubMed Central)
  48. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, Hiebert SW (2008) Mol Cell 30(1): 61-72
    › Primary publication · 18406327 (PubMed) · PMC2373760 (PubMed Central)
  49. Cyclin-dependent kinase 2 dependent phosphorylation of ATRIP regulates the G2-M checkpoint response to DNA damage. Myers JS, Zhao R, Xu X, Ham AJ, Cortez D (2007) Cancer Res 67(14): 6685-90
    › Primary publication · 17638878 (PubMed) · PMC2728292 (PubMed Central)
  50. Function of the ATR N-terminal domain revealed by an ATM/ATR chimera. Chen X, Zhao R, Glick GG, Cortez D (2007) Exp Cell Res 313(8): 1667-74
    › Primary publication · 17376433 (PubMed) · PMC1855264 (PubMed Central)
  51. Function of a conserved checkpoint recruitment domain in ATRIP proteins. Ball HL, Ehrhardt MR, Mordes DA, Glick GG, Chazin WJ, Cortez D (2007) Mol Cell Biol 27(9): 3367-77
    › Primary publication · 17339343 (PubMed) · PMC1899971 (PubMed Central)
  52. DDB1 maintains genome integrity through regulation of Cdt1. Lovejoy CA, Lock K, Yenamandra A, Cortez D (2006) Mol Cell Biol 26(21): 7977-90
    › Primary publication · 16940174 (PubMed) · PMC1636754 (PubMed Central)
  53. Rapid activation of ATR by ionizing radiation requires ATM and Mre11. Myers JS, Cortez D (2006) J Biol Chem 281(14): 9346-50
    › Primary publication · 16431910 (PubMed) · PMC1821075 (PubMed Central)
  54. ATRIP oligomerization is required for ATR-dependent checkpoint signaling. Ball HL, Cortez D (2005) J Biol Chem 280(36): 31390-6
    › Primary publication · 16027118 (PubMed) · PMC1360181 (PubMed Central)
  55. Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling. Cortez D (2005) Genes Dev 19(9): 1007-12
    › Primary publication · 15879550 (PubMed) · PMC1360198 (PubMed Central)
  56. ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylation. Ball HL, Myers JS, Cortez D (2005) Mol Biol Cell 16(5): 2372-81
    › Primary publication · 15743907 (PubMed) · PMC1087242 (PubMed Central)
  57. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Cortez D, Glick G, Elledge SJ (2004) Proc Natl Acad Sci U S A 101(27): 10078-83
    › Primary publication · 15210935 (PubMed) · PMC454167 (PubMed Central)
  58. Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases. Cortez D (2003) J Biol Chem 278(39): 37139-45
    › Primary publication · 12847089 (PubMed)
  59. Direct DNA binding by Brca1. Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M (2001) Proc Natl Acad Sci U S A 98(11): 6086-91
    › Primary publication · 11353843 (PubMed) · PMC33426 (PubMed Central)
  60. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT (2000) Genes Dev 14(23): 2989-3002
    › Primary publication · 11114888 (PubMed) · PMC317107 (PubMed Central)
  61. Conducting the mitotic symphony. Cortez D, Elledge SJ (2000) Nature 406(6794): 354-6
    › Primary publication · 10935617 (PubMed)
  62. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, Pendergast AM (1998) Genes Dev 12(10): 1415-24
    › Primary publication · 9585502 (PubMed) · PMC316832 (PubMed Central)
  63. A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS (1998) Genes Dev 12(7): 968-81
    › Primary publication · 9531535 (PubMed) · PMC316671 (PubMed Central)
  64. The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells. Cortez D, Reuther G, Pendergast AM (1997) Oncogene 15(19): 2333-42
    › Primary publication · 9393877 (PubMed)
  65. The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway. Cortez D, Stoica G, Pierce JH, Pendergast AM (1996) Oncogene 13(12): 2589-94
    › Primary publication · 9000132 (PubMed)
  66. Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis. Cortez D, Kadlec L, Pendergast AM (1995) Mol Cell Biol 15(10): 5531-41
    › Primary publication · 7565705 (PubMed) · PMC230804 (PubMed Central)
  67. Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation. Gishizky ML, Cortez D, Pendergast AM (1995) Proc Natl Acad Sci U S A 92(24): 10889-93
    › Primary publication · 7479904 (PubMed) · PMC40536 (PubMed Central)