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Thomas                         Melendy

Thomas E. Melendy PhD

Department of Microbiology and Immunology

Associate Professor of Microbiology & Biochemistry

Specialty/Research Focus

Virology

 
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Professional Summary:

-The research interests of my laboratory are focused on the mechanism of human DNA replication and how DNA replication is controlled. We use model viral DNA replication systems, such as simian virus 40 (SV40) and papillomaviruses, both of which can replicate their DNA in human cells, as well as biochemical studies of human cellular proteins. Our studies on the mechanisms and regulation of DNA replication are intimately linked to our studies on novel papillomavirus and cellular DNA replication factors as well as our studies on how DNA damage inhibits DNA replication.

Our studies on papillomavirus DNA replication are focused on identifying cellular proteins that papillomaviruses require to replicate their DNA. I have previously shown that all the cellular factors required for in vitro SV40 DNA replication are also required for papillomavirus DNA replication in vitro. However, they are not sufficient; additional cellular factors are required to support papillomavirus DNA replication. We are currently using a reconstitution assay to begin to purify those factors from human cells. In addition, a complementation assay, first developed in Dr. Louise Chow‘s laboratory at the University of Alabama at Birmingham, is currently being used to identify cellular factors in human 293 cell extracts that can complement human HeLa cell extracts for in vitro papillomavirus DNA replication.

One of the ways in which we are studying the mechanism of DNA replication is by looking at the protein-protein interactions that take place between DNA replication factors at the replication fork. I previously demonstrated that an interaction between SV40-T -antigen (the viral DNA replication protein) and the human Replication Protein A complex appears to be important for priming during DNA synthesis. We are now studying the interactions between the papillomavirus DNA replication proteins and known cellular replication factors. Future plans include evaluating the biological significance of these interactions.

Another search for novel human DNA replication factors entails the identification of human factors that are involved in the priming stages of DNA replication. We have utilized a novel priming inactivation assay to identify such an activity and are currently purifying this new DNA replication factor. Identification of this factor is very important in that this factor is apparently not required for current in vitro DNA replication systems which are based on SV40 and papillomaviruses.

We have recently entered into a collaboration with Dr. Terry Beerman‘s laboratory at Roswell Park Cancer Institute to study the molecular effects of anticancer drugs on DNA replication. Dr. Beerman‘s laboratory has recently shown that a certain class of new chemotherapeutic anticancer drugs acts to block cellular DNA replication at very low levels of drug. This response seems to be similar to the very potent DNA damage dependent DNA replication arrest seen with ionizing radiation. We are currently investigating the mechanism by which these drugs inhibit DNA replication. In addition to elucidating how these anticancer drugs act to arrest cancer cell growth, we believe these studies will provide general information about how cells arrest DNA replication in response to DNA damage.

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)
  • Adjunct Assistant Professor, University at Buffalo (1995–2001)
  • Assistant Professor, University at Buffalo (1994–2000)
  • Post Doctoral Fellow, Cold Spring Harbor Laboratories (1988–1994)
Awards and Honors:
  • 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)
  • Damon Runyon-Walter Winchell Postdoctoral Cancer Research Fellowship (1991)
  • Ursula Mandel Fellowship for Biomedical Research (1988)
  • 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)

Grants and Sponsored Research:
  • January 2001–December 2005
    Mechanisms of DNA damage-triggered S phase checkpoints
    National Institutes of Health
    Role: Principal Investigator
    $169,000
  • September 1999–August 2004
    HPV DNA replication: novel host factors
    National Institutes of Health
    Role: Principal Investigator
    $482,129
  • September 1999–August 2004
    Training in microbial pathogenesis
    National Institutes of Health
    Role: Co-Investigator
    $162,556
  • 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
    $74,770
  • 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
    $43,013
  • 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 (12 Total) >

Journal Articles:
  • Liu, J.-S., Kuo, S.-K., Beerman, T.A., Melendy T. Induction of DNA damage responses by adozelesin is S phase-specific and dependent on active replication forks. Molec. Cancer Therapeutics. 2003; 2.
  • Melendy T, Li R. Chromatin remodeling and initiation of DNA replication.. Front Biosci. 2001; 6.
  • McHugh MM, Yin X, Kuo SR, Liu JS, Melendy T, Beerman TA. The cellular response to DNA damage induced by the enediynes C-1027 and neocarzinostatin includes hyperphosphorylation and increased nuclear retention of replication protein a (RPA) and trans inhibition of DNA replication.. Biochemistry. 2001; 40(15).
  • Dziegielewski J, Melendy T, Beerman TA. Bleomycin-induced alterations in DNA replication: relationship to DNA damage.. Biochemistry. 2001; 40(3).
  • J.S. Liu, S.R. Kuo, X. Yin, T. A. Beerman, Thomas Melendy. Damage by the Enediyne, C-1027, Results in the Inhibition of DNA Replication by Loss of Replication Protein a Function and Activation of DNA-Dependent Protein Kinase. Biochemistry. 2001; 40.
  • Loo YM, Melendy T. The majority of human replication protein A remains complexed throughout the cell cycle.. Nucleic Acids Res. 2000; 28(17).
  • Liu JS, Kuo SR, McHugh MM, Beerman TA, Melendy T. Adozelesin triggers DNA damage response pathways and arrests SV40 DNA replication through replication protein A inactivation.. J Biol Chem. 2000; 275(2).
  • McHugh MM, Kuo SR, Walsh-O'Beirne MH, Liu JS, Melendy T, Beerman TA. Bizelesin, a bifunctional cyclopropylpyrroloindole alkylating agent, inhibits simian virus 40 replication in trans by induction of an inhibitor.. Biochemistry. 1999; 38(35).
  • Dimitrova DS, Todorov IT, Melendy T, Gilbert DM. Mcm2, but not RPA, is a component of the mammalian early G1-phase prereplication complex.. J Cell Biol. 1999; 146(4).
  • Han Y, Loo YM, Militello KT, Melendy T. Interactions of the papovavirus DNA replication initiator proteins, bovine papillomavirus type 1 E1 and simian virus 40 large T antigen, with human replication protein A.. J Virol. 1999; 73(6).
  • Ni TH, McDonald WF, Zolotukhin I, Melendy T, Waga S, Stillman B, Muzyczka N. Cellular proteins required for adeno-associated virus DNA replication in the absence of adenovirus coinfection.. J Virol. 1998; 72(4).
  • Simmons DT, Melendy T, Usher D, Stillman B. Simian virus 40 large T antigen binds to topoisomerase I.. Virology. 1996; 222(2).
  • Melendy T, Sedman J, Stenlund A. Cellular factors required for papillomavirus DNA replication.. J Virol. 1995; 69(12).
  • Wun-Kim K, Upson R, Young W, Melendy T, Stillman B, Simmons DT. The DNA-binding domain of simian virus 40 tumor antigen has multiple functions.. J Virol. 1993; 67(12).
  • Brown GW, Melendy T, Ray DS. Replication protein A from the trypanosomatid Crithidia fasciculata is inactive in the primosome assembly step of SV40 DNA replication.. Mol Biochem Parasitol. 1993; 59(2).
  • Melendy T, Stillman B. An interaction between replication protein A and SV40 T antigen appears essential for primosome assembly during SV40 DNA replication.. J Biol Chem. 1993; 268(5).
  • Brown GW, Melendy TE, Ray DS. Conservation of structure and function of DNA replication protein A in the trypanosomatid Crithidia fasciculata.. Proc Natl Acad Sci U S A. 1992; 89(21).
  • Melendy T, Stillman B. Purification of DNA polymerase delta as an essential simian virus 40 DNA replication factor.. J Biol Chem. 1991; 266(3).
  • Tsurimoto T, Melendy T, Stillman B. Sequential initiation of lagging and leading strand synthesis by two different polymerase complexes at the SV40 DNA replication origin.. Nature. 1990; 346(6284).
  • Melendy T, Ray DS. Novobiocin affinity purification of a mitochondrial type II topoisomerase from the trypanosomatid Crithidia fasciculata.. J Biol Chem. 1989; 264(3).
  • Sheline C, Melendy T, Ray DS. Replication of DNA minicircles in kinetoplasts isolated from Crithidia fasciculata: structure of nascent minicircles.. Mol Cell Biol. 1989; 9(1).
  • Melendy T, Sheline C, Ray DS. Localization of a type II DNA topoisomerase to two sites at the periphery of the kinetoplast DNA of Crithidia fasciculata.. Cell. 1988; 55(6).
  • Melendy T, Ray DS. Purification and nuclear localization of a type I topoisomerase from Crithidia fasciculata.. Mol Biochem Parasitol. 1987; 24(2).
See All (23 Total) >

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) >

Clinical Specialties:
Clinical Offices:
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Contact Information

213 Biomedical Research Building
Buffalo, NY 14214
Phone: (716) 829-3381
Email: tmelendy@buffalo.edu


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