Genome Maintenance Research Program

Changes to the genome are at the epicenter of cancer mechanisms and response to therapies. The Genome Maintenance Research Program is a cohesive network of basic science researchers focused on understanding how DNA is damaged, repaired, packaged, expressed, and replicated.

RESEARCH THEMES

Members of the Genome Maintenance Program have expertise across all of the major processes involved in the faithful maintenance and expression of the genetic material:

Carcinogen Metabolism

How environmental agents and the products of natural cellular metabolism cause mutations and lead to cancer

Chromatin & Epigenetics

How the epigenome contributes to genome integrity and expression and how it goes awry in cancer

DNA Damage Response

How DNA damage response pathways are activated and how they function to maintain genome integrity and suppress cancer

DNA Metabolism

How DNA damage is repaired and how defects in these processes lead to cancer

Gene Expression

How control of gene expression is central to normal cellular homeostasis and cancer mechanisms

Meet the Program Members

Co-led by David Cortez, Ph.D., and William Tansey, Ph.D., the Genome Maintenance program includes faculty members from over a dozen departments and centers across campus. Research interests of our members are broad and encompassing — from control of DNA replication and mitosis to mechanisms of DNA damage, DNA damage response and repair, chromatin, epigenetics, and the regulation of gene activity. This vibrant group of researchers harbors expertise in biochemistry, cell biology, genetics, genomics, model organisms, proteomics, and structural biology. Their specific research strengths, together with a common focus on the genome, creates a highly synergistic environment where both formal and informal collaborations thrive and bolster our research accomplishments and impact.

Program Leader

David K. Cortez, Ph.D.

Program Leader

William P. Tansey, Ph.D.

All Program Members

Featured Publications

Replication Fork Uncoupling Causes Nascent Strand Degradation and Fork Reversal.

Kavlashvili, T., Liu, W., Mohamed, T.M., Cortez, D. (GM) & Dewar, J.M. (GM).

Nat Struct Mol Biol 2023; PMID:36593312.

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Human SMARCA5 is Continuously Required to Maintain Nucleosome Spacing.

Bomber, M.L., Wang, J., Liu, Q., Barnett, K.R., Layden, H.M., Hodges, E. (GM), Stengel, K.R. & Hiebert, S.W. (GM).

Mol Cell 2023; PMID:36630954.

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Hotspot of de novo Telomere Addition Stabilizes Linear Amplicons in Yeast Grown in Sulfate-limiting Conditions.

Hoerr, R.E., Eng, A., Payen, C., Di Rienzi, S.C., Raghuraman, M.K., Dunham, M.J., Brewer, B.J. & Friedman, K.L. (GM).

Genetics 2023; PMID:36702776.

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RTEL1 and MCM10 Overcome Topological Stress During Vertebrate Replication Termination.

Campos, L.V., Van Ravenstein, S.X., Vontalge, E.J., Greer, B.H., Heintzman, D.R., Kavlashvili, T., McDonald, W.H., Rose, K.L., Eichman, B.F. (GM) & Dewar, J.M. (GM).

Cell Rep 42(2):112109, 2023; PMID:36807139.

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Direct Visualization of Transcription-replication Conflicts Reveals Post-replicative DNA:RNA Hybrids.

Stoy, H., Zwicky, K., Kuster, D., Lang, K.S., Krietsch, J., Crossley, M.P., Schmid, J.A., Cimprich, K.A., Merrikh, H. (GM) & Lopes, M.

Nat Struct Mol Biol 2023; PMID:36864174.

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Nucleophosmin Plays a Role in Repairing DNA Damage and is a Target for Cancer Treatment.

Sekhar, K.R. & Freeman, M.L. (GM).

Cancer Res 2023; PMID:36877156.

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Human and Bacterial TatD Enzymes Exhibit Apurinic/Apyrimidinic (AP) Endonuclease Activity.

Dorival, J. & Eichman, B.F. (GM).

Nucleic Acids Res 2023; PMID:36881763.

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RAD51 Bypasses the CMG Helicase to Promote Replication Fork Reversal.

Liu, W., Saito, Y., Jackson, J., Bhowmick, R., Kanemaki, M.T., Vindigni, A. & Cortez, D. (GM).

Science 380(6643):382, 2023; PMID:37104614.

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Aminopyridine Analogs Selectively Target Metastatic Pancreatic Cancer.

Smalling, R.V., Bechard, M.E., Duryea, J., Kingsley, P.J., Roberts, E.R., Marnett, L.J. (GM), Bilbao, D., Stauffer, S.R. & McDonald, O.G.

Oncogene 2022; PMID:35031771.

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WIN Site Inhibition Disrupts a Subset of WDR5 Function.

Siladi, A.J., Wang, J., Florian, A.C., Thomas, L.R., Creighton, J.H., Matlock, B.K., Flaherty, D.K., Lorey, S.L., Howard, G.C., Fesik, S.W. (CB), Weissmiller, A.M., Liu, Q. & Tansey, W.P. (GM).

Sci Rep 12(1):1848, 2022; PMID:35115608.

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Oligomerization of DNA Replication Regulatory Protein RADX is Essential to Maintain Replication Fork Stability.

Mohamed, T., Adolph, M.B. & Cortez, D. (GM).

J Biol Chem :101672, 2022; PMID:35120927.

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Base Excision Repair System Targeting DNA Adducts of Trioxacarcin/LL-D49194 Antibiotics for Self-resistance.

Chen, X., Bradley, N.P., Lu, W., Wahl, K.L., Zhang, M., Yuan, H., Hou, X.F., Eichman, B.F. (GM) & Tang, G.L.

Nucleic Acids Res 2022; PMID:35191495.

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Synergistic Action of WDR5 and HDM2 Inhibitors in SMARCB1-deficient Cancer Cells.

Florian, A.C., Woodley, C.M., Wang, J., Grieb, B.C., Slota, M.J., Guerrazzi, K., Hsu, C.Y., Matlock, B.K., Flaherty, D.K., Lorey, S.L., Fesik, S.W. (CB), Howard, G.C., Liu, Q., Weissmiller, A.M. & Tansey, W.P. (GM).

NAR Cancer 4(1):zcac007, 2022; PMC8892060.

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CHK1 Phosphorylates PRIMPOL to Promote Replication Stress Tolerance.

Mehta, K.P.M., Thada, V., Zhao, R., Krishnamoorthy, A., Leser, M., Lindsey Rose, K. & Cortez, D. (GM).

Sci Adv 8(13):eabm0314, 2022; PMID:35353580.

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Identification of Replication Fork-associated Proteins in Drosophila Embryos and Cultured Cells Using iPOND Coupled to Quantitative Mass Spectrometry.

Munden, A., Wright, M.T., Han, D., Tirgar, R., Plate, L. & Nordman, J.T. (GM).

Sci Rep 12(1):6903, 2022; PMID:35484306.

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MTG16 (CBFA2T3) Regulates Colonic Epithelial Differentiation, Colitis, and Tumorigenesis by Repressing E Protein Transcription Factors.

Brown, R.E., Jacobse, J., Anant, S.A., Blunt, K.M., Chen, B., Vega, P.N., Jones, C.T., Pilat, J.M., Revetta, F., Gorby, A.H., Stengel, K.R., Choksi, Y.A. (GI), Palin, K., Piazuelo, M.B. (GI), Washington, M.K. (GI), Lau, K.S. (CB), Goettel, J.A., Hiebert, S.W. (GM), Short, S.P. & Williams, C.S. (GI).

JCI Insight 2022; PMID:35503250.

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Topoisomerase II Poisons Inhibit Vertebrate DNA Replication Through Distinct Mechanisms.

Van Ravenstein, S.X., Mehta, K.P., Kavlashvili, T., Byl, J.A.W., Zhao, R., Osheroff, N. (GM), Cortez, D. (GM) & Dewar, J.M. (GM).

EMBO J :e110632, 2022; PMID:35578785.

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An Active Learning Framework Improves Tumor Variant Interpretation.

Blee, A.M., Li, B. (CE), Pecen, T., Meiler, J. (CB), Nagel, Z.D., Capra, J.A. & Chazin, W.J. (GM).

Cancer Res 2022; PMID:35687855.

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Ligand-independent Integrin Beta1 Signaling Supports Lung Adenocarcinoma Development.

Haake, S.M. (TR), Plosa, E.J., Kropski, J.A., Venton, L.A., Reddy, A., Bock, F., Chang, B.T., Luna, A.J., Nabukhotna, K., Xu, Z.Q., Prather, R.A., Lee, S., Tanjore, H., Polosukhin, V.V., Viquez, O.M., Jones, A., Luo, W., Wilson, M.H., Rathmell, W.K. (GM), Massion, P.P., Pozzi, A. (HT), Blackwell, T.S. (TR) & Zent, R. (HT).

JCI Insight 2022; PMID:35763345.

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ATAC-STARR-seq Reveals Transcription Factor-bound Activators and Silencers Across the Chromatin Accessible Human Genome.

Hansen, T.J. & Hodges, E. (GM).

Genome Res 2022; PMID:35858748.

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The SOS Response-associated Peptidase (SRAP) Domain of YedK Catalyzes Ring Opening of Abasic Sites and Reversal of its DNA-protein Crosslink.

Paulin, K.A., Cortez, D. (GM) & Eichman, B.F. (GM).

J Biol Chem :102307, 2022; PMID:35934051.

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Two Interaction Surfaces Between XPA and RPA Organize the Preincision Complex in Nucleotide Excision Repair.

Kim, M., Kim, H.S., D'Souza, A., Gallagher, K., Jeong, E., Topolska-Wós, A., Ogorodnik Le Meur, K., Tsai, C.L., Tsai, M.S., Kee, M., Tainer, J.A., Yeo, J.E., Chazin, W.J. (GM) & Schärer, O.D.

Proc Natl Acad Sci U S A 119(34):e2207408119, 2022; PMID:35969784.

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Nucleoporins Facilitate ORC Loading onto Chromatin.

Richards, L., Lord, C.L., Benton, M.L., Capra, J.A. & Nordman, J.T. (GM).

Cell Rep 41(6):111590, 2022; PMID:36351393.

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PAX3-FOXO1 Coordinates Enhancer Architecture, eRNA Transcription, and RNA Polymerase Pause Release at Select Gene Targets.

Zhang, S., Wang, J., Liu, Q., McDonald, W.H., Bomber, M.L., Layden, H.M., Ellis, J., Borinstein, S.C. (TR), Hiebert, S.W. (GM) & Stengel, K.R.

Mol Cell 2022; PMID:36395771.

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SETD2 Regulates the Methylation of Translation Elongation Factor eEF1A1 in Clear Cell Renal Cell Carcinoma.

Hapke, R., Venton, L., Rose, K.L., Sheng, Q., Reddy, A., Prather, R., Jones, A., Rathmell, W.K. (GM) & Haake, S.M. (TR).

Kidney Cancer J 6(3):179, 2022; PMC9851421.

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Structure-based Discovery of Potent WD Repeat Domain 5 Inhibitors that Demonstrate Efficacy and Safety in Preclinical Animal Models.

Teuscher, K.B., Chowdhury, S., Meyers, K.M., Tian, J., Sai, J., Van Meveren, M., South, T.M., Sensintaffar, J.L., Rietz, T.A., Goswami, S., Wang, J., Grieb, B.C., Lorey, S.L., Howard, G.C., Liu, Q., Moore, W.J., Stott, G.M., Tansey, W.P. (GM), Lee, T. & Fesik, S.W. (CB).

Proc Natl Acad Sci U S A 120(1):e2211297120, 2022; PMID:36574664.

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Program News

February 23, 2023

Study explores new urinary tract infection treatment

Vanderbilt's Neil Osheroff, PhD, is part of an international research collaboration resulting in what is on track to be the first new antibiotic treatment for uncomplicated urinary tract infections in more than 20 years.

May 23, 2023

Research Snapshot: DNA replication discovery opens pathways to understanding and treating cancer, aging and degenerative disease

An international collaboration led by biochemist David Cortez reached revelatory conclusions in exploration of how cells tolerate DNA damage and genome instability. Est. reading time: 2 mins.

October 25, 2023

VUMC to help engage more study participants in research decisions

Human research will be more equitable, inclusive and stronger if the people who are participants in studies also help plan and guide the direction of those studies.

More Program News