David K. Cortez, Ph.D.
- Associate Director for Basic Science Research
- Co-Leader, Genome Maintenance Research Program
- Richard Armstrong Professor of Biochemistry
- Chair and Professor of Biochemistry
Phone
613 Light Hall
Nashville, TN 37232-0146
David K. Cortez, Ph.D.
- Associate Director for Basic Science Research
- Co-Leader, Genome Maintenance Research Program
- Richard Armstrong Professor of Biochemistry
- Chair and Professor of Biochemistry
615-322-8547
david.cortez@vanderbilt.edu
613 Light Hall
Nashville, TN 37232-0146
Research Program
Departments/Affiliations
Profile
Education
Research Emphasis
Genome maintenance by the DNA damage response, cell cycle, DNA replication, DNA repair, cancer, proteomics, cell biology, genome editing, biochemistry, genetics, mass spectrometry, CRISPR-Cas9, signaling, kinase, toxicology, chemical biology
Research Description
Billions of base pairs of DNA must be replicated trillions of times during a human lifetime. Adding to the difficulty, thousands of DNA lesions happen in each cell of our body every day. Furthermore, replication is challenged by difficult to replicate sequences and conflicts with transcription. DNA damage response mechanisms act to repair the damaged DNA, signal checkpoint activation, ensure completion of DNA replication, and maintain genome stability. Defects in these mechanisms can cause developmental abnormalities, premature aging, and cancer.
The Cortez lab is dedicated to understanding the mechanisms that maintain genome integrity and promote the complete and accurate replication of the genome.
Current projects in the lab include:
1. Discovery of new replication, repair, and DNA damage response proteins using genetic screens and proteomics
2. Characterization of replication fork remodeling and fork protection proteins related to the BRCA1/BRCA2 pathway
3. Understanding sources of genome instability in normal and cancer cells
4. Analysis of DNA damage signaling pathways controlled by the ATR kinase
5. Development of cancer therapeutic approaches targeting the DNA damage response
6. Characterization of mechanisms that repair abasic sites generated by endogenous and environmental mutagens
We use a multi-disciplinary approach including genetics, biochemistry, cell biology, proteomics, and structural biology. The lab is part of the Genome Maintenance Program within the Vanderbilt-Ingram Cancer Center, Center in Molecular Toxicology, Vanderbilt Institute of Chemical Biology, and Department of Biochemistry.
SIGNIFICANCE
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, developmental abnormalities, and other diseases. 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. Discovering the mechanisms by which cells respond to DNA damage and other types of replication stress will provide insights into the etiology of diseases like cancer as well as identify opportunities for therapeutic intervention.
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Publications
- Paulin KA, Cortez D, Eichman BF. The SOS response-associated peptidase (SRAP) domain of YedK catalyzes ring opening of abasic sites and reversal of its DNA-protein crosslink. J Biol Chem [print-electronic]. 2022 Aug 8/4/2022; 102307. PMID: 35934051, PII: S0021-9258(22)00749-9, DOI: 10.1016/j.jbc.2022.102307, ISSN: 1083-351X.
- Van Ravenstein SX, Mehta KP, Kavlashvili T, Byl JAW, Zhao R, Osheroff N, Cortez D, Dewar JM. Topoisomerase II poisons inhibit vertebrate DNA replication through distinct mechanisms. EMBO J [print-electronic]. 2022 Jun 6/14/2022; 41(12): e110632. PMID: 35578785, PMCID: PMC9194788, DOI: 10.15252/embj.2022110632, ISSN: 1460-2075.
- Mehta KPM, Thada V, Zhao R, Krishnamoorthy A, Leser M, Lindsey Rose K, Cortez D. CHK1 phosphorylates PRIMPOL to promote replication stress tolerance. Sci Adv [print-electronic]. 2022 Apr; 8(13): eabm0314. PMID: 35353580, PMCID: PMC8967226, DOI: 10.1126/sciadv.abm0314, ISSN: 2375-2548.
- Mohamed T, Adolph MB, Cortez D. Oligomerization of DNA replication regulatory protein RADX is essential to maintain replication fork stability. J Biol Chem [print-electronic]. 2022 Mar; 298(3): 101672. PMID: 35120927, PMCID: PMC8902620, PII: S0021-9258(22)00112-0, DOI: 10.1016/j.jbc.2022.101672, ISSN: 1083-351X.
- Krishnamoorthy A, Jackson J, Mohamed T, Adolph M, Vindigni A, Cortez D. RADX prevents genome instability by confining replication fork reversal to stalled forks. Mol Cell [print-electronic]. 2021 May 5/29/2021; PMID: 34107305, PII: S1097-2765(21)00390-7, DOI: 10.1016/j.molcel.2021.05.014, ISSN: 1097-4164.
- Adolph MB, Mohamed TM, Balakrishnan S, Xue C, Morati F, Modesti M, Greene EC, Chazin WJ, Cortez D. RADX controls RAD51 filament dynamics to regulate replication fork stability. Mol Cell [print-electronic]. 2021 Mar 3/4/2021; 81(5): 1074-1083.e5. PMID: 33453169, PMCID: PMC7935748, PII: S1097-2765(20)30957-6, DOI: 10.1016/j.molcel.2020.12.036, ISSN: 1097-4164.
- Thada V, Cortez D. ATR activation is regulated by dimerization of ATR activating proteins. J Biol Chem [print-electronic]. 2021 Feb 2/23/2021; 100455. PMID: 33636182, PMCID: PMC7994790, PII: S0021-9258(21)00228-3, DOI: 10.1016/j.jbc.2021.100455, ISSN: 1083-351X.
- Liu W, Krishnamoorthy A, Zhao R, Cortez D. Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors. Sci Adv [electronic-print]. 2020 Nov; 6(46): PMID: 33188024, PMCID: PMC7673757, PII: 6/46/eabc3598, DOI: 10.1126/sciadv.abc3598, ISSN: 2375-2548.
- Berti M, Cortez D, Lopes M. The plasticity of DNA replication forks in response to clinically relevant genotoxic stress. Nat Rev Mol Cell Biol [print-electronic]. 2020 Oct; 21(10): 633-51. PMID: 32612242, PII: 10.1038/s41580-020-0257-5, DOI: 10.1038/s41580-020-0257-5, ISSN: 1471-0080.
- Berti M, Cortez D, Lopes M. The plasticity of DNA replication forks in response to clinically relevant genotoxic stress. Nat. Rev. Mol. Cell Biol [print-electronic]. 2020 Jul 7/1/2020; PMID: 32612242, PII: 10.1038/s41580-020-0257-5, DOI: 10.1038/s41580-020-0257-5, ISSN: 1471-0080.
