Photo of Donald M. Coen,  PhD

Donald M. Coen, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-1691
Fax: (617) 432-3833

Donald M. Coen, PhD

Harvard Medical School


  • Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School


Research Abstract

The Coen laboratory takes molecular approaches to herpesviruses, especially to understand processes that distinguish viral functions from cellular functions, which can be exploited to permit antiviral therapy. Although much of the research involves herpes simplex virus (HSV), which is not an oncogenic virus, many of the findings apply to oncogenic herpesviruses and to biological processes and drug discovery strategies relevant to cancer in general.

The foci of the laboratory are 1) regulation of expression of viral genes, 2) functional dissection of replication proteins, 3) analysis of virus latency, a fascinating and clinically important topic, 4) antiviral drug targets, drug mechanisms, and drug resistance. In the first area, we study novel post-transcriptional regulatory mechanisms in the HSV system, including ribosomal frameshifting on thymidine kinase mRNAs from drug-resistant mutants, antisense regulation, and regulated

polyadenylation. In the second area, we focus on herpesvirus DNA polymerases, which are both antiviral drug targets and prototypes for eukaryotic replicative polymerases. We use antiviral drug resistance to help dissect amino acid residues involved in the the different steps of polymerization; explore the interactions of polymerases with processivity proteins via mutational and biophysical approaches; and have been determining how the processivity factors function via a novel mechanism involving direct DNA binding. These studies should permit detailed

understanding of these complicated enzymes and rational drug design, particularly to interrupt protein-protein interactions.

In the third area, latency and pathogenesis, we use virus mutants and PCR-based methods to explore gene function and regulation (e.g. checkpoints for repressing gene expression) and the state of viral DNA during latency. We are also studying the interaction of HSV with the central nervous system with implications for the use of HSV-based therapies for nervous system diseases such as brain tumors. In the fourth area, antiviral drug targets, mechanisms, and resistance, aside from the studies mentioned above, we are exploiting the human cytomegalovirus protein

kinase that phosphorylates ganciclovir to aid the design of better antiviral drugs, and are finding new drug targets primarily by analyzing drug-resistant mutants.

Publications from Harvard Catalyst Profiles

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  • Sun B, Yang X, Hou F, Yu X, Wang Q, Oh HS, Raja P, Pesola JM, Vanni EAH, McCarron S, Morris-Love J, Ng AHM, Church GM, Knipe DM, Coen DM, Pan D. Regulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency. Nat Microbiol 2021. PubMed
  • Chen H, Lawler JL, Filman DJ, Hogle JM, Coen DM. Resistance to a Nucleoside Analog Antiviral Drug from More Rapid Extension of Drug-Containing Primers. MBio 2021. PubMed
  • Griffante G, Gugliesi F, Pasquero S, Dell'Oste V, Biolatti M, Salinger AJ, Mondal S, Thompson PR, Weerapana E, Lebbink RJ, Soppe JA, Stamminger T, Girault V, Pichlmair A, Oroszlán G, Coen DM, De Andrea M, Landolfo S. Human cytomegalovirus-induced host protein citrullination is crucial for viral replication. Nat Commun 2021; 12:3910. PubMed
  • Sen P, Wilkie AR, Ji F, Yang Y, Taylor IJ, Velazquez-Palafox M, Vanni EAH, Pesola JM, Fernandez R, Chen H, Morsett LM, Abels ER, Piper M, Lane RJ, Hickman SE, Means TK, Rosenberg ES, Sadreyev RI, Li B, Coen DM, Fishman JA, El Khoury J. Linking indirect effects of cytomegalovirus in transplantation to modulation of monocyte innate immune function. Sci Adv 2020; 6:eaax9856. PubMed
  • Kim ET, Roche KL, Kulej K, Spruce LA, Seeholzer SH, Coen DM, Diaz-Griffero F, Murphy EA, Weitzman MD. SAMHD1 Modulates Early Steps during Human Cytomegalovirus Infection by Limiting NF-κB Activation. Cell Rep 2019; 28:434-448.e6. PubMed
  • Pan D, Li G, Morris-Love J, Qi S, Feng L, Mertens ME, Jurak I, Knipe DM, Coen DM. Herpes Simplex Virus 1 Lytic Infection Blocks MicroRNA (miRNA) Biogenesis at the Stage of Nuclear Export of Pre-miRNAs. MBio 2019. PubMed
  • Lawler JL, Coen DM. HSV-1 DNA polymerase 3'-5' exonuclease-deficient mutant D368A exhibits severely reduced viral DNA synthesis and polymerase expression. J Gen Virol 2018; 99:1432-1437. PubMed
  • Lee JS, Raja P, Pan D, Pesola JM, Coen DM, Knipe DM. CCCTC-Binding Factor Acts as a Heterochromatin Barrier on Herpes Simplex Viral Latent Chromatin and Contributes to Poised Latent Infection. MBio 2018. PubMed
  • Wilkie AR, Sharma M, Pesola JM, Ericsson M, Fernandez R, Coen DM. A role for myosin Va in human cytomegalovirus nuclear egress. J Virol 2018. PubMed
  • Lawler JL, Mukherjee P, Coen DM. HSV-1 DNA Polymerase RNase H Activity Acts in a 3' -5' Direction and is Dependent on the 3' -5' Exonuclease Active Site. J Virol 2017. PubMed
  • Lutz G, Jurak I, Kim ET, Kim JY, Hackenberg M, Leader A, Stoller ML, Fekete DM, Weitzman MD, Coen DM, Wilson AC. Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors. Viruses 2017. PubMed
  • Chen H, Coseno M, Ficarro SB, Mansueto MS, Komazin-Meredith G, Boissel S, Filman DJ, Marto JA, Hogle JM, Coen DM. A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions. ACS Infect Dis 2017; 3:112-118. PubMed
  • Pan D, Pesola JM, Li G, McCarron S, Coen DM. Mutations Inactivating Herpes Simplex Virus 1 MicroRNA miR-H2 Do Not Detectably Increase ICP0 Gene Expression in Infected Cultured Cells or Mouse Trigeminal Ganglia. J Virol 2017. PubMed
  • Lye MF, Wilkie AR, Filman DJ, Hogle JM, Coen DM. Getting to and through the inner nuclear membrane during herpesvirus nuclear egress. Curr Opin Cell Biol 2017; 46:9-16. PubMed
  • Polachek WS, Moshrif HF, Franti M, Coen DM, Sreenu VB, Strang BL. High-Throughput Small Interfering RNA Screening Identifies Phosphatidylinositol 3-Kinase Class II Alpha as Important for Production of Human Cytomegalovirus Virions. J Virol 2016; 90:8360-71. PubMed
  • Chen H, Li C, Zemlicka J, Gentry BG, Bowlin TL, Coen DM. Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase. Antimicrob Agents Chemother 2016; 60:4176-82. PubMed
  • Colgrove RC, Liu X, Griffiths A, Raja P, Deluca NA, Newman RM, Coen DM, Knipe DM. History and genomic sequence analysis of the herpes simplex virus 1 KOS and KOS1.1 sub-strains. Virology 2016; 487:215-21. PubMed
  • Sharma M, Kamil JP, Coen DM. Preparation of the Human Cytomegalovirus Nuclear Egress Complex and Associated Proteins. Methods Enzymol 2016; 569:517-26. PubMed
  • Raja P, Lee JS, Pan D, Pesola JM, Coen DM, Knipe DM. A Herpesviral Lytic Protein Regulates the Structure of Latent Viral Chromatin. MBio 2016. PubMed
  • Wilkie AR, Lawler JL, Coen DM. A Role for Nuclear F-Actin Induction in Human Cytomegalovirus Nuclear Egress. MBio 2016. PubMed
  • Lye MF, Sharma M, El Omari K, Filman DJ, Schuermann JP, Hogle JM, Coen DM. Unexpected features and mechanism of heterodimer formation of a herpesvirus nuclear egress complex. EMBO J 2015; 34:2937-52. PubMed
  • Leigh KE, Sharma M, Mansueto MS, Boeszoermenyi A, Filman DJ, Hogle JM, Wagner G, Coen DM, Arthanari H. Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication. Proc Natl Acad Sci U S A 2015. PubMed
  • Sharma M, Bender BJ, Kamil JP, Lye MF, Pesola JM, Reim NI, Hogle JM, Coen DM. Human cytomegalovirus UL97 phosphorylates the viral nuclear egress complex. J Virol 2015. PubMed
  • Chen H, Beardsley GP, Coen DM. Mechanism of ganciclovir-induced chain termination revealed by resistant viral polymerase mutants with reduced exonuclease activity. Proc Natl Acad Sci U S A 2014; 111:17462-7. PubMed
  • Bender BJ, Coen DM, Strang BL. Dynamic and nucleolin-dependent localization of human cytomegalovirus UL84 to the periphery of viral replication compartments and nucleoli. J Virol 2014; 88:11738-47. PubMed
  • Sharma M, Coen DM. Comparison of effects of inhibitors of viral and cellular protein kinases on human cytomegalovirus disruption of nuclear lamina and nuclear egress. J Virol 2014; 88:10982-5. PubMed
  • Pan D, Flores O, Umbach JL, Pesola JM, Bentley P, Rosato PC, Leib DA, Cullen BR, Coen DM. A neuron-specific host microRNA targets herpes simplex virus-1 ICP0 expression and promotes latency. Cell Host Microbe 2014; 15:446-56. PubMed
  • Terrell SL, Pesola JM, Coen DM. Roles of conserved residues within the pre-NH2-terminal domain of herpes simplex virus 1 DNA polymerase in replication and latency in mice. J Gen Virol 2014; 95:940-7. PubMed
  • Jurak I, Hackenberg M, Kim JY, Pesola JM, Everett RD, Preston CM, Wilson AC, Coen DM. Expression of herpes simplex virus 1 microRNAs in cell culture models of quiescent and latent infection. J Virol 2014; 88:2337-9. PubMed
  • Pan D, Kaye SB, Hopkins M, Kirwan R, Hart IJ, Coen DM. Common and new acyclovir resistant herpes simplex virus-1 mutants causing bilateral recurrent herpetic keratitis in an immunocompetent patient. J Infect Dis 2014; 209:345-9. PubMed
  • Sharma M, Kamil JP, Coughlin M, Reim NI, Coen DM. Human cytomegalovirus UL50 and UL53 recruit viral protein kinase UL97, not protein kinase C, for disruption of nuclear lamina and nuclear egress in infected cells. J Virol 2014; 88:249-62. PubMed
  • Yan Z, Bryant KF, Gregory SM, Angelova M, Dreyfus DH, Zhao XZ, Coen DM, Burke TR, Knipe DM. HIV integrase inhibitors block replication of alpha-, beta-, and gammaherpesviruses. MBio 2014; 5:e01318-14. PubMed
  • Reim NI, Kamil JP, Wang D, Lin A, Sharma M, Ericsson M, Pesola JM, Golan DE, Coen DM. Inactivation of retinoblastoma protein does not overcome the requirement for human cytomegalovirus UL97 in lamina disruption and nuclear egress. J Virol 2013; 87:5019-27. PubMed
  • Cliffe AR, Coen DM, Knipe DM. Kinetics of facultative heterochromatin and polycomb group protein association with the herpes simplex viral genome during establishment of latent infection. MBio 2013. PubMed
  • Terrell SL, Coen DM. The pre-NH(2)-terminal domain of the herpes simplex virus 1 DNA polymerase catalytic subunit is required for efficient viral replication. J Virol 2012; 86:11057-65. PubMed
  • Strang BL, Bender BJ, Sharma M, Pesola JM, Sanders RL, Spector DH, Coen DM. A mutation deleting sequences encoding the amino terminus of human cytomegalovirus UL84 impairs interaction with UL44 and capsid localization. J Virol 2012; 86:11066-77. PubMed
  • Pan D, Coen DM. Net -1 frameshifting on a noncanonical sequence in a herpes simplex virus drug-resistant mutant is stimulated by nonstop mRNA. Proc Natl Acad Sci U S A 2012; 109:14852-7. PubMed
  • Jurak I, Silverstein LB, Sharma M, Coen DM. Herpes simplex virus is equipped with RNA- and protein-based mechanisms to repress expression of ATRX, an effector of intrinsic immunity. J Virol 2012; 86:10093-102. PubMed
  • Weller SK, Coen DM. Herpes simplex viruses: mechanisms of DNA replication. Cold Spring Harb Perspect Biol 2012; 4:a013011. PubMed
  • Silva LA, Loregian A, Pari GS, Strang BL, Coen DM. The carboxy-terminal segment of the human cytomegalovirus DNA polymerase accessory subunit UL44 is crucial for viral replication. J Virol 2010; 84:11563-8. PubMed
  • Tran K, Kamil JP, Coen DM, Spector DH. Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1. J Virol 2010; 84:10832-43. PubMed
  • Strang BL, Geballe AP, Coen DM. Association Of Human Cytomegalovirus Proteins IRS1 And TRS1 With The Viral DNA Polymerase Accessory Subunit UL44. J Gen Virol 2010; 91:2167-75. PubMed
  • Strang BL, Coen DM. Interaction of the Human Cytomegalovirus Uracil DNA Glycosylase UL114 with the Viral DNA Polymerase Catalytic Subunit UL54. J Gen Virol 2010; 91:2029-33. PubMed
  • Gentry BG, Kamil JP, Coen DM, Zemlicka J, Drach JC. Stereoselective phosphorylation of cyclopropavir by pUL97 and competitive inhibition by maribavir. Antimicrob Agents Chemother 2010; 54:3093-8. PubMed
  • Jurak I, Kramer MF, Mellor JC, van Lint AL, Roth FP, Knipe DM, Coen DM. Numerous Conserved and Divergent MicroRNAs Expressed by Herpes Simplex Viruses 1 and 2. J Virol 2010; 84:4659-72. PubMed
  • Strang BL, Boulant S, Coen DM. Nucleolin associates with the human cytomegalovirus DNA polymerase accessory subunit UL44 and is necessary for efficient viral replication. J Virol 2010; 84:1771-84. PubMed
  • Baltz JL, Filman DJ, Ciustea M, Silverman JE, Lautenschlager CL, Coen DM, Ricciardi RP, Hogle JM. The crystal structure of PF-8, the DNA polymerase accessory subunit from Kaposi's sarcoma-associated herpesvirus. J Virol 2009; 83:12215-28. PubMed
  • Kamil JP, Hume AJ, Jurak I, Münger K, Kalejta RF, Coen DM. Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase. Proc Natl Acad Sci U S A 2009; 106:16823-8. PubMed
  • Jiang C,Komazin-Meredith G,Tian W,Coen DM,Hwang CB. Mutations that Increase DNA binding by the Processivity Factor of Herpes Simplex Virus Affect Virus Production and DNA Replication Fidelity. J Virol 2009; 83:7573-80. PubMed
  • Strang BL,Sinigalia E,Silva LA,Coen DM,Loregian A. Analysis of the Association of the Human Cytomegalovirus DNA Polymerase Subunit UL44 with the Viral DNA Replication Factor UL84. J Virol 2009; 83:7581-9. PubMed
  • Sam MD,Evans BT,Coen DM,Hogle JM. Biochemical, biophysical, and mutational analyses of subunit interactions of the human cytomegalovirus nuclear egress complex. J Virol 2009; 83:2996-3006. PubMed
  • Hamirally S,Kamil JP,Ndassa-Colday YM,Lin AJ,Jahng WJ,Baek MC,Noton S,Silva LA,Simpson-Holley M,Knipe DM,Golan DE,Marto JA,Coen DM. Viral mimicry of Cdc2/cyclin-dependent kinase 1 mediates disruption of nuclear lamina during human cytomegalovirus nuclear egress. PLoS Pathog 2009; 5:e1000275. PubMed
  • Sinigalia E,Alvisi G,Mercorelli B,Coen DM,Pari GS,Jans DA,Ripalti A,Palu G,Loregian A. Role of homodimerization of human cytomegalovirus DNA polymerase accessory protein UL44 in origin-dependent DNA replication in cells. J Virol 2008; 82:12574-9. PubMed
  • Bryant KF,Macari ER,Malik N,Boyce M,Yuan J,Coen DM. ICP34.5-dependent and -independent activities of salubrinal in herpes simplex virus-1 infected cells. Virology 2008; 379:197-204. PubMed
  • Umbach JL,Kramer MF,Jurak I,Karnowski HW,Coen DM,Cullen BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 2008; 454:780-3. PubMed
  • Komazin-Meredith G,Petrella RJ,Santos WL,Filman DJ,Hogle JM,Verdine GL,Karplus M,Coen DM. The human cytomegalovirus UL44 C clamp wraps around DNA. Structure 2008; 16:1214-25. PubMed
  • Hume AJ, Finkel JS, Kamil JP, Coen DM, Culbertson MR, Kalejta RF. Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function. Science 2008; 320:797-9. PubMed
  • Komazin-Meredith G, Santos WL, Filman DJ, Hogle JM, Verdine GL, Coen DM. The positively charged surface of herpes simplex virus UL42 mediates DNA binding. J Biol Chem 2008; 283:6154-61. PubMed
  • Bryant KF, Coen DM. Inhibition of translation by a short element in the 5' leader of the herpes simplex virus 1 DNA polymerase transcript. J Virol 2008; 82:77-85. PubMed
  • Jiang C, Hwang YT, Wang G, Randell JC, Coen DM, Hwang CB. Herpes simplex virus mutants with multiple substitutions affecting DNA binding of UL42 are impaired for viral replication and DNA synthesis. J Virol 2007; 81:12077-9. PubMed
  • Kamil JP, Coen DM. Human cytomegalovirus protein kinase UL97 forms a complex with the tegument phosphoprotein pp65. J Virol 2007; 81:10659-68. PubMed
  • Dodson AW, Taylor TJ, Knipe DM, Coen DM. Inhibitors of the sodium potassium ATPase that impair herpes simplex virus replication identified via a chemical screening approach. Virology 2007; 366:340-8. PubMed
  • Besecker MI, Furness CL, Coen DM, Griffiths A. Expression of extremely low levels of thymidine kinase from an acyclovir-resistant herpes simplex virus mutant supports reactivation from latently infected mouse trigeminal ganglia. J Virol 2007; 81:8356-60. PubMed
  • Pesola JM, Coen DM. In vivo fitness and virulence of a drug-resistant herpes simplex virus 1 mutant. J Gen Virol 2007; 88:1410-4. PubMed
  • Jiang C, Hwang YT, Randell JC, Coen DM, Hwang CB. Mutations that decrease DNA binding of the processivity factor of the herpes simplex virus DNA polymerase reduce viral yield, alter the kinetics of viral DNA replication, and decrease the fidelity of DNA replication. J Virol 2007; 81:3495-502. PubMed
  • Loregian A, Sinigalia E, Mercorelli B, Palu G, Coen DM. Binding parameters and thermodynamics of the interaction of the human cytomegalovirus DNA polymerase accessory protein, UL44, with DNA: implications for the processivity mechanism. Nucleic Acids Res 2007; 35:4779-91. PubMed
  • Griffiths A, Link MA, Furness CL, Coen DM. Low-level expression and reversion both contribute to reactivation of herpes simplex virus drug-resistant mutants with mutations on homopolymeric sequences in thymidine kinase. J Virol 2006; 80:6568-74. PubMed
  • Cui C, Griffiths A, Li G, Silva LM, Kramer MF, Gaasterland T, Wang XJ, Coen DM. Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 2006; 80:5499-508. PubMed