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Thomas                         Melendy

Thomas Melendy PhD

Department of Microbiology and Immunology

Associate Professor (with tenure) of Microbiology & Immunology, and Biochemistry

Specialty/Research Focus

DNA Replication, Recombination and Repair; Genome Integrity; Infectious Disease; Microbiology; Molecular and Cellular Biology; Molecular genetics; Virology

 
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Professional Summary:

The major focus of my laboratory is in understanding the molecular machines that make up the DNA replication forks of the small human DNA viruses, polyoma- and papillomaviruses. Specifically, this means elucidating the dynamic protein-protein interactions that allow the series of enzymes required to replicate DNA to act in concert and in the correct sequence required to duplicate the genome. Both papillomaviruses and polyomaviruses are human pathogens, HPV resulting in a vast number of human cancers, and the human polyomaviruses, JC and BK, causing serious disease and death in immunocompromised patients. Both viral systems also provide important models for the study of human DNA replication mechanisms. Both viral systems have led to vital insights into eukaryotic DNA replication, with the study of polyomavirus DNA replication leading to the first identification of many cellular DNA replication complexes and processes, and more recently papillomavirus providing the best structures and models to date of replicative hexameric DNA helicases and how they function.
There are two primary areas that my laboratory is currently focused on. One is elucidating the dynamic protein-protein interactions that take place between proteins at the DNA replication fork and understanding how they function to carry out DNA replication. My laboratory has been at the forefront of identifying the interactions between the one critical HPV DNA replication protein, the origin-binding DNA helicase, E1, and cellular DNA replication proteins. Understanding these interactions and how they help support the overall DNA replication process has helped our understanding of, and continues to lead to information that tells us more about how eukaryotic DNA replication forks function. In addition, as we identify protein-protein interactions between HPV E1 and cellular factors that are essential for HPV DNA synthesis, this identifies potential targets for development of broad-range HPV anti-virals that could act to block HPV replication. I have recently obtained a large multi-laboratory NIH research grant to investigate just this possibility for the interaction between HPV E1 and the human DNA replication protein, Topoisomerase I. As we identify and characterize additional vital interactions between E1 and cellular replication factors this will lead to more potential anti-viral targets.
The second primary area of investigation is elucidating how the cellular DNA damage response (DDR) pathways inhibit DNA replication when cells are subjected to DNA damage. For many years the DDR field focused on the effects of DDR on the cell cycle kinases as the only method by which DNA replication was arrested. In the mid- to late-2000’s it became recognized that in mammalian cells there is also a substantial inhibition (10-fold) of elongation of DNA replication following DDR. The mechanisms for this inhibition are currently unknown. Using both in vitro and cell-based SV40 DNA replication systems we have shown that SV40 DNA replication is also shut down in response to DDR kinase pathways, and this is not based on cell cycle kinase action. Therefore SV40 provides a vital model system for determining how elongation of DNA replication is inhibited by DDR. Furthermore, we have shown that in contrast, HPV DNA replication does not respond to DDR, providing us an important control DNA replication system for these studies. (The lack of DDR arrest of HPV DNA replication likely explains why HPV integrates so readily into host cell chromosomes - an important step for HPV-induced carcinogenesis). Our studies on the DDR effect on polyoma and papilloma virus DNA replication will lead to insights into the effect of DDR on cellular DNA replication, and into how HPV integrates into host cell chromosomes causing HPV-induced cancers.

Education and Training:
  • PhD, Molecular Biology, University of California at Los Angeles (1988)
  • BS, Biological Sciences (Microbiology), Cornell University (1983)
Employment:
  • Associate Professor, University at Buffalo (2000-present)
  • Associate Professor, University at Buffalo (2000-present)
  • Adjunct Assistant Professor, University at Buffalo (1996-present)
  • Senior Lecturer, with tenure, Henry Wellcome Institute of Comparative Medicine, University of Glasgow, School of Veterinary Medicine, Scotland (2007–2008)
  • consultant, KuDOS division of Astra Zeneca, United Kingdom (2007–2008)
  • consultant, Roche Discovery Welwyn, United Kingdom (1999–2002)
  • Adjunct Assistant Professor, University at Buffalo (1995–2001)
  • Assistant Professor tenure track, University at Buffalo (1994–2000)
  • Post Doctoral Fellow, Cold Spring Harbor Laboratories (1988–1994)
Awards and Honors:
  • UB Teaching Innovation Award (2013)
  • Roche Award (2010)
  • Lifetime Fellow AAAS (2006)
  • K02 - Nat‘l Institutes of Health, National Institute of Allergy & Infectious Dise (2004)
  • First Invited Speaker for the University of Rochester DNA Replication & Rep (2000)
  • Nat'l Cancer Institute Conference Grant Travel Award (1999)
  • American Cancer Society Research Scholar Award (1998)
  • American Cancer Society postdoctoral fellowship (declined) (1989)
  • Damon Runyon-Walter Winchell Postdoctoral Cancer Research Fellowship (1989)
  • Ursula Mandel Fellowship for Biomedical Research (1987)
  • Nat'l Institutes of Health, Nat'l Cancer Institute Pre-doctoral Training Gr (1987)
  • University of California at Los Angeles University Fellowship (1984)
  • United States Presidential Scholar, US Department of Education (1979)
  • National Merit Scholarship Finalist (1979)

Research Centers:
  • Witebsky Center for Microbial Pathogenesis and Immunology
UB 2020 Strategic Strengths:
  • Molecular Recognition in Biological Systems and Bioinformatics
Grants and Sponsored Research:
  • September 2014–August 2017
    Functional Interactions of HPV Replication Proteins E1 and E2 with Cellular DNA Proteins
    NIH
    Role: Co-Principal Investigator
    $83,976
  • April 2012–March 2016
    Evaluation and Development of E1-TopoI as a target for anti-HPV therapeutics
    NiAID
    Role: Principal Investigator
    $1,739,194
  • January 2001–December 2005
    Mechanisms of DNA damage-triggered S phase checkpoints
    National Institutes of Health
    Role: Principal Investigator
    $1,406,570
  • September 1999–August 2004
    Training in microbial pathogenesis
    National Institutes of Health
    Role: Co-Investigator
    $162,556
  • September 1999–August 2004
    HPV DNA replication: novel host factors
    National Institutes of Health
    Role: Principal Investigator
    $482,130
  • April 2000–May 2003
    DNA replication arrest and DNA damage responses induced by AMGBs
    US Army Breat Cancer Initiative
    Role: Consultant
    $143,855
  • August 1997–July 2002
    Papillomavirus DNA replication: host cell factors
    National Institutes of Health
    Role: Principal Investigator
    $538,421
  • July 2001–June 2002
    UB Graduate Group Award
    Buffalo DNA Replication Graduate Group
    Role: Co-Principal Investigator
    $3,000
  • January 1998–December 2001
    Cellular initiation proteins in eukaryotic DNA replication
    American Cancer Society
    Role: Principal Investigator
    $396,000
  • November 1999–October 2001
    HPV DNA replication inhibitors
    Roche Discovery Welwyn
    Role: Principal Investigator
    $48,000
  • May 1999–June 2000
    Effects of alkylating minor groove binders on DNA replication
    UB Multidisciplinary Pilot Project Program
    Role: Principal Investigator
    $19,867
  • April 1998–March 1999
    The relationship between cellular responses to DNA damaging antitumor agents and inhibition of DNA replication
    Role: Co-Investigator
    $148,000
  • May 1997–August 1998
    Cell-cycle localization and association of the human Replication Protein A subunits
    UB Multidisciplinary Pilot Project Program
    Role: Principal Investigator
    $20,000
  • May 1995–June 1996
    Role of viral glycoproteins in infectious entry
    Role: Co-Investigator
    $19,235
See All (14 Total) >

Journal Articles:
See All (39 Total) >
Abstracts:
  • Tezal M, Sullivan MA, Stoler D, Hyland A, Melendy TE, Smaldino PJ, Rigual N, Loree T. Chronic Periodontitis, Smoking and Human Papillomavirus 16 Interaction in Base of Tongue Cancers. Arch Otolaryngol Head Neck Surg. 2008.

Professional Memberships:
  • American Society of Microbiology (1998)
  • Buffalo Collegium of Immunology (1995)
  • Western New York, American Society for Microbiology (1995)
  • American Association for the Advancement of Science (1992)
Presentations:
  • "DNA replication-dependent and -independent mechanisms for DNA damage-induced intra-nuclear redistribution and hyper-phosphorylation of Replication Protein A" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (2001)
  • "Recruitment of cellular Replication Protein A by the papillomavirus E1 protein" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (2001)
  • "DNA replication-dependent and -independent mechanisms for DNA damage-induced intra-nuclear focalization and hyper-phosphorylation of Replication Protein A." Nuclear Structure & Cancer, FASEB (2001)
  • "DNA damage-induced RPA foci formation and hyperphosphorylation in S phase cells" Fifth Annual Buffalo DNA Replication & Repair Symposium, Roswell Park Cancer Institute (2001)
  • "Recruitment of cellular Replication Protein A by the papillomavirus E1 protein" Fifth Annual Buffalo DNA Replication & Repair Symposium, Roswell Park Cancer Institute (2001)
  • "Different DNA damaging agents trigger different DNA replication inhibition mechanisms" Eukaryotic DNA Replication Meeting, The Salk Institute (2000)
  • "In vitro okazaki fragment synthesis by human DNA polymerase alpha requires a Cdc45 protein complex" Eukaryotic DNA Replication Meeting, The Salk Institute (2000)
  • "The majority of human Replication Protein A remains complexed throughout the Cell Cycle" Eukaryotic DNA Replication Meeting, The Salk Institute (2000)
  • "Different DNA damaging agents trigger different S-phase checkpoint/DNA replication inhibition mechanisms" LXV Cold Spring Harbor Symposium on Quantitative Biology, Biological Responses to DNA Damage (2000)
  • "Different DNA damaging agents trigger S-phase checkpoint/DNA replication inhibition mechanisms" Buffalo DNA Replication Graduate Group Fourth Annual Symposium (2000)
  • "Purification of a Cdc45-containing complex that recruits DNA polymerase alpha-primase in the presence of hRPA in vitro" Buffalo DNA Replication Group Fourth Annual Symposiium (2000)
  • "Purification of a Cdc45-containing complex that recruits DNA polymerase alpha/primase in the presence of hRPA invitro" Buffalo DNA Replication Graduate Group Fourth Annual Symposium (2000)
  • "DNA damage triggers multiple mechanisms of DNA replication arrest" University of Rochester, Department of Biochemistry and Biophysics (2000)
  • "DNA damage triggers multiple mechanisms of DNA replication arrest" First Meeting of the DNA Replication and Repair Cluster, University of Rochester School of Medicine, DNA Replication and Repair Cluster (2000)
  • "Genotoxic Chemotherapeutics Trigger Multiple S-Phase Checkpoint Mechanisms" University of Virginia, Department of Biochemistry and Molecular Genetics (2000)
  • "Multiple Mechanisms of DNA Replication Arrest are Triggered by DNA Damaging Anti-Cancer Chemotherapeutics" University of Delaware, Department of Biological Sciences (1999)
  • "Multiple mechanisms of inhibition of SV40 DNA replication following DNA damage" Roswell Park Cancer Institute, DNA Damage Group monthly meeting (1999)
  • "Bovine Papillomavirus Type 1 E1 Protein Interacts with Human Replication Protein A" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1999)
  • "DNA damaging anti-cancer agents trigger multiple S-phase checkpoints" University at Buffalo, SUNY, Center for Advanced Molecular Biology & Immunology Research Exchange Series (1999)
  • "DNA replication arrest by adozelesin is through inactivation of replication protein A" Cold Spring Habor Meeting on Eukaryotic DNA Replication (1999)
  • "Purification of a Human Cellular DNA Polymerase Alpha/Primase Stimulatory Factor" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1999)
  • "Mechanisms of SV40 DNA Replication Arrest After Treatment of Cells with DNA-Damaging Agents." Tumour Virus Meeting on Polyomaviruses, Papillomaviruses and Adenoviruses, Imperial Cancer Research Fund (1999)
  • "Multiple Mechanisms of DNA Replication Arrest are Induced by DNA Damaging Chemotherapeutic Agents" University of Massachusetts, Department of Biochemistry (1999)
  • "Purification of a Human Celular DNA Polymerase Alpha-Primase Stimulatory Factor" Buffalo DNA Replication Graduate Group Third Annual Symposiuim (1999)
  • "Trigger DNA Damage-Dependent DNA Replication Arrest Through more than one Mechanism" Buffalo DNA Replication Graduate Group Third Annual Symposium (1999)
  • "Novel Mechanisms of Papillomavirus DNA Replication In Vitro." 17th International Papillomavirus Conference (1999)
  • "Protein interactions with the cellular single-stranded DNA binding complex, replication protein A" Buffalo DNA Replication Graduate Group Third Annual Symposium (1999)
  • "Identification of Novel Eukaryotic DNA Replication Factors: A Cellular Primosome Activity from Human Cells" Eukaryotic DNA Replication (1998)
  • "Identification of Novel Eukaryotic DNA Replication Factors: A Cellular Primosome Activity from Human Cells" Buffalo DNA Replicatiion Graduate Group Second Annual Symposium (1998)
  • "Viral appropriation of the cellular DNA replication machinery" University at Buffalo, SUNY, Microbial Pathogenesis Graduate Group Meeting (1997)
  • "Different papovaviruses utilize common mechanisms to take over the cellular DNA replication machinery" NICHD symposium on THE Eukaryotic Nucleus (1997)
  • "Papovavirus DNA replication initiator proteins bind similarly to Replication Protein A" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1997)
  • "Mechanisms of Papovavirus DNA Replication" University of California at Los Angeles, Molecular Biology Institute (1997)
  • "Mechanisms of Papovavirus DNA Replication" University at Buffalo, SUNY, Department of Biological Sciences (1996)
  • "Eukaryotic factors required for papillomavirus DNA replication" University at Buffalo, SUNY, CAMBI Research Exchange Series (1995)
  • "Ceullar factors required for papillomavirus DNA replication" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1995)
  • "Requirements of cellular factors for papillomavirus DNA replication" University at Buffalo, SUNY, Department of Biochemistry (1995)
  • "Different cellular factors are required for PV and SV40 DNA replication in vitro" Roswell Park Cancer Institute, Department of Molecular and Cellular Biology (1994)
  • "Papillomavirus DNA replication: what else is needed?" University at Buffalo, SUNY, Department of Microbiology (1994)
  • "In vitro replication of papillomavirus DNA requires human cellular factors other than those required for SV40 DNA replication" Meeting on Molecular Biology of SV40, Polyoma, and Adenovirus, Cold Spring Harbor Meeting (1994)
  • "SV40 large T antigen binds to human topoisomerase I" Meeting on Molecular Biology of SV40, Polyoma, and Adenovirus, Cold Spring Harbor Meeting (1994)
  • "Simian Virus 40 and Papillomavirus: Mechanisms of Genome Replication" Wayne State University, Department of Microbiology and Immunology (1994)
  • "Simian Virus 40 and Papillomavirus: Mechanisms of Genome Replication" Temple University School of Medicine, Fels Institute for Cancer Research (1994)
  • "Simian Virus 40 and papillomavirus: Mechanisms of Genome Replication" University of Buffalo, SUNY, Department of Microbiology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" University of Minnesota, Department of Pharmacology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" University of Michigan, Department of Microbiology and Immunology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" Yale University School of Medicine, Department of Therapeutic Radiology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" St. Louis University, Department of Biology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" University at Buffalo, SUNY, Department of Biochemistry (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" National Institutes of Health, National Institute of Child Health & Development, Laboratory of Molecular Growth and Regulation (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" Texas A & M University, Albert B. Alkek Institute of Biosciences and Technology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" University of Maryland College Park, Department of Microbiology (1993)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" University of Medicine & Dentistry of New Jersey, Department of Biochemistry (1992)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" Thomas Jefferson Medical School (1992)
  • "SV40 DNA replication." Molecular Biology of SV40, Polyoma, and Adenovirus (1992)
  • "Simian Virus 40 DNA Replication: Mechanisms and Approaches" Harvard Medical School, Massachusetts General Hospital East, Cutaneous Biology Research Center (1992)
  • "Phosphorylation of RPA p34 and its role in DNA replication" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1991)
  • "Cell-ctcle specific phosphorylation by cdc2 kinase of RF-A, a cellular protein essential for DNA replication from the SV40 origin of replication" Tumor Virus Meeting on SV40, Polyoma, and Adenovirus, Cold Spring Harbor Meeting (1990)
  • "Cellular replication factors sequentially direct the in vitro initiation of leading and lagging strand DNA synthesis by two DNA polymerases at the SV40 origin." Tumor Virus Meeting on SV40, Polyoma, and Adenovirus (1990)
  • "Functions of proteins involved in SV40 DNA replication in vitro" Cold Spring Harbor Meeting on EukaryoticDNA Replication (1989)
  • "Kinetoplast DNA topoisomerase II" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1989)
  • "Replication of SV40 DNA and chromatin assembly in vitro" Cold Spring Harbor Meeting on Eukaryotic DNA Replication (1989)
  • "A homogeneous type II topoisomerase from the trypanosomatid Crithidia fasciculata" Sixth Cold Spring Harbor Meeting on Cancer Cells (1987)
  • "Topoisomerases in the trypanosomatid, Crithidia fasciculata" First West Coast Parasitology Meeting (1987)
  • "Topoisomerases in the trypanosomatid, Crithidia fasciculata" First West Coast Parasitology Meeting (1987)
  • "Topoisomerase I in Crithidia fasciculata" UCLA symposia on molecular and cellular biology (1986)
See All (66 Total) >
Service Activities:
  • School of Medicine & Biomedical Sciences Phase I; Member (2010)
  • School of Medicine & Biomedical Sciences Apppointment, Promotions,Tenure & Privileges; Member (2009–2012)
  • School of Medicine & Biomedical Sciences Apppointment, Promotions,Tenure & Privileges; Member (2003–2006)

Clinical Specialties:
Clinical Offices:
Insurance Accepted:

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Contact Information

213 Biomedical Research Building
School of Medicine & Biomedical Sciences
3435 Main Street
Buffalo, NY 14214
Phone: (716) 829-3789
Email: tmelendy@buffalo.edu


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