Anna Marie Skalka, PhD

Anna Marie Skalka, PhD

Senior Advisor to the President

Professor Emerita

Former W.W. Smith Chair in Cancer Research

Lab Overview

Work in the Skalka laboratory has been focused on obtaining a detailed understanding of the mechanism by which retroviral DNA is integrated into its host cell chromatin, and discovering the epigenetic factors and processes that affect its subsequent expression. Retroviruses are of special interest, not only because they are agents of disease, including cancer, but also because they are important as vehicles for the insertion of desired genes into target cells for scientific investigation and gene therapy.

A broad range of investigational methods have been exploited in these studies from analyses of protein function, to in vivo studies of viral growth and cell biology. Our overarching goals have been to uncover new information of fundamental importance to both virus and cell biology, and to identify new targets for therapies to treat disease.

  • The single cell reproductive cycle of the alpharetrovirus, ALV. The virus life cycle is 46divided into an early phase that includes steps from virus infection to establishment of the provirus, and a late phase that includes expression of the provirus and formation of progeny virions. Adapted from: Principles of Virology, 4rd edition Vol. I. 2015. S.J Flint, V.R Racaniello, G.F. Rall. and A.M. Skalka. ASM Press Washington DC, Vol. I Appendix, Figure 30.

    Slide 1 The single cell reproductive cycle of the alpharetrovirus, ALV. The virus life cycle is 46 divided into an early phase that includes steps from virus infection to establishment of the provirus, and a late phase that includes expression of the provirus and formation of progeny virions. Adapted from: Principles of Virology, 4rd edition Vol. I. 2015. S.J Flint, V.R Racaniello, G.F. Rall. and A.M. Skalka. ASM Press Washington DC, Vol. I Appendix, Figure 30.

  • Steps in the synthesis of retroviral DNA and its integration into host DNA. The viral RNA genome (green line) is reverse transcribed in the cytoplasm of the cell within a subviral nucleoprotein structure (called the reverse transcription complex) to form a duplex DNA containing long terminal repeats (LTRs) of sequences unique to the 5 (U5) and 3 (U3) ends of the viral RNA. The organization of the genes common to all retroviruses ( gag, pro, pol, and env) is colinear with the RNA genome.

    Slide 2 Steps in the synthesis of retroviral DNA and its integration into host DNA. The viral RNA genome (green line) is reverse transcribed in the cytoplasm of the cell within a subviral nucleoprotein structure (called the reverse transcription complex) to form a duplex DNA containing long terminal repeats (LTRs) of sequences unique to the 5 (U5) and 3 (U3) ends of the viral RNA. The organization of the genes common to all retroviruses ( gag, pro, pol, and env) is colinear with the RNA genome. Imperfect inverted repeats at the LTR duplex termini are recognized and nicked by cognate integrase (IN) proteins, following a conserved CA dinucleotide at each 3 end ( purple arrowheads in inset), producing recessed 3-OH ends. This first reaction catalyzed by IN is called processing and takes place within a nucleoprotein assembly called a preintegration complex. A tetramer of IN bound to the processed viral DNA (vDNA) ends enters the nucleus, where a joining reaction catalyzed by IN connects the 3-OH ends of the vDNA to staggered phosphates at a target site in the host DNA. The length of the stagger (4–6 bp) is characteristic of the viral IN protein. The conserved CA dinucleotide and steps catalyzed by IN are highlighted in purple. Removal of the noncomplementary 5 nucleotides of vDNA and repair of the gaps in host DNA by host enzymes generate a covalently integrated provirus, shorter by 2 bp on either end and flanked by duplications of the target site (red arrows). From: MD Andrake and AM Skalka, Retroviral Integrase: Then and Now. Ann. Rev. Virol. Vol.2. 2015.

  • Domain organization of integrase (IN) proteins from different retroviruses. (a) Maps for the organization of IN proteins from the alpharetrovirus avian sarcoma/leukosis virus (ASLV), the gammaretrovirus murine leukemia virus (MLV), the lentivirus human immunodeficiency virus type 1 (HIV-1), and the spumavirus prototype foamy virus (PFV). Amino acid numbers delineate the start and end of each domain: the N-terminal extension domain (NED; purple); the N-terminal domain (NTD; red )

    Slide 3 Domain organization of integrase (IN) proteins from different retroviruses. (a) Maps for the organization of IN proteins from the alpharetrovirus avian sarcoma/leukosis virus (ASLV), the gammaretrovirus murine leukemia virus (MLV), the lentivirus human immunodeficiency virus type 1 (HIV-1), and the spumavirus prototype foamy virus (PFV). Amino acid numbers delineate the start and end of each domain: the N-terminal extension domain (NED; purple); the N-terminal domain (NTD; red ), including the HHCC motif; the catalytic core domain (CCD; blue), including the D,D(35)E motif; and the C-terminal domain (CTD; green). The lengths of linkers that connect the domains are indicated below the lines between domains. Domains for which there is no experimentally determined structure from crystallography are in muted colors. (b) Domain models from crystal structures of the HIV-1 NTD (PDB 1K6Y), CCD (PDB 1BIU), and CTD (PDB 1EX4). The Zn2+ ion in the NTD is shown as an aqua sphere; one of the two Mg2+ ions bound in the active site of the CCD is shown as a green sphere. The conserved Glu residue of the D,D(35)E motif is presumed to chelate the second metal ion together with the first conserved Asp residue. From: MD Andrake and AM Skalka, Retroviral Integrase: Then and Now. Ann. Rev. Virol. Vol.2. 2015.

  • Models for architectures of full-length human immunodeficiency virus type 1 (HIV-1) apo-integrase (IN) protein in solution.

    Slide 4 Models for architectures of full-length human immunodeficiency virus type 1 (HIV-1) apo-integrase (IN) protein in solution. (a) Structures for HIV-1 IN protein in the absence of DNA substrates were derived by HADDOCK data-driven modeling of the HIV-1 IN monomer, dimer, and tetramer in solution, based on small-angle X-ray scattering and protein cross-linking data. Catalytic core domains (CCDs) are rendered in muted surface representation to emphasize their locations in the structures. It is not yet known which of these forms is competent for the viral DNA binding that leads to assembly of an HIV-1 intasome. (b) An HIV-1 intasome model (90) with DNA shown in yellow ladder representation. Structures, colored as in Figure 3, are in a ribbon rendering and were generated using Chimera software. From: MD Andrake and AM Skalka, Retroviral Integrase: Then and Now. Ann. Rev. Virol. Vol.2. 2015.

  • Model for the roles of the human Daxx protein in the initiation and maintenance of epigenetic silencing. Daxx acts as a scaffolding protein to recruit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) to avian sarcoma virus (ASV) DNA via binding to integrase (IN). Bottom- Post-integration repressive marks are depicted as circles. The mechanism by which Daxx is positions on viral DNA to during silencing maintenance is unknow, as indicated by the question mark.

    Slide 5 Model for the roles of the human Daxx protein in the initiation and maintenance of epigenetic silencing. Daxx acts as a scaffolding protein to recruit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) to avian sarcoma virus (ASV) DNA via binding to integrase (IN). Bottom- Post-integration repressive marks are depicted as circles. The mechanism by which Daxx is positions on viral DNA to during silencing maintenance is unknow, as indicated by the question mark. Black rectangles = long terminal repeats (LTRs) in retroviral DNA. See: Shalginskikh N. et al. Retroviral DNA methylation ond epigeneic repression are mediated by the antiviral host protein Daxx. J. Virol. 87:2137.2013.

  • Skalka lab staff, 2015

    Skalka lab staff, 2015: George Merkel, Kate Buettner, Maria Shubina, Valentina Medvedeva, Richard Katz, Alison Beister, Adam Maynard, Jason Wasserman, Mark Andrake Marie Estes

    Educational Background

    • Postdoctoral Fellow, Genetics, Carnegie Insitution, Cold Spring Harbor, NY
    • PhD, Candidate, Microbiology, Yale University, New Haven CT, 1959-60
    • PhD, Microbiology, New York University Medical School, New York, NY
    • BA, Biology, Adelphi University, Garden City, NY, 1959

     

    Memberships

    • Editorial Board, Journal of Virology, 1974 - 1985
    • NIH Working Group on Safer Hosts and Vectors, (for Recombinant DNA Research), Recombinant DNA Advisory Committee   1976 - 1980
    • Editor, Gene, 1976 - 1997
    • Member, Memorial Sloan-Kettering Cancer Center,  Standing Committee on Recombinant DNA Research, 1977 - 1979
    • NIH Study Section, Experimental Virology, 1977 - 1981
    • IUPHAR (International Union of Pharmacology), Representative to the International Congress of Scientific Union's Committee on Genetic Experimentation (COGENE), 1977 - 1985
    • Member, American Cancer Society Advisory Committee  on Microbiology and Virology, 1982 - 1985
    • Editorial Board, Journal of Molecular and Cellular Biology, 1983 - 1987
    • Commissioner, New Jersey State Commission on Cancer Research, (Governor's Appointment), 1983 - date
    • Editor, BioEssay, 1984 - 1989
    • Editor, Journal of Virology, 1985 – 1989
    • Outstanding Woman Scientist Award,  American Association of Women in Science, 1985
    • Member, Board of Scientific Counselors for National Institute of Diabetes, Digestive and Kidney Diseases, 1989 - 1993
    • Member, General Motors Cancer Research Foundation Awards Assembly, 1989 - 1993
    • Chairperson, 1991 Sloan Prize Selection Committee, 1990
    • National Cancer Institute, Outstanding Investigator Grant, 1990-1997
    • Recipient, Bristol-Myers Squibb Special Unrestricted Grant, Research in Infectious Diseases, 1992-1997
    • Member, External Advisory Board, NCI-designated Comprehensive Cancer Center, Albert Einstein College of Medicine, NY, 1992 - 1995
    • Member, Selection Committee for Bristol-Myers Squibb Award, Outstanding Achievement in Infectious Diseases, 1992 - 1997
    • Chair, Scientific Advisory Board, NCI designated Cancer Center, McArdle Laboratory for Cancer Research, Madison, WI, 1992 - 1999
    • Editorial Board, Cancer Research, 1993 – 2005
    • Elected, American Academy of Arts and Sciences, 1994
    • Chair, Microbiological and Immunological Special Emphasis Panel, Experimental Virology Study Section, 1994 - 1995
    • Member, NCI Board of Scientific Counselors, Division of Cancer Treatment, 1994 - 1995
    • Editorial Board, Journal of Biological Chemistry, 1994 - 2006
    • Member, Selection Committee, Chiron Corporation Biotechnology Research Award, 1995 - 1998
    • Member, Scientific Advisory Board, Case Western Reserve University, Center for AIDS Research, 1995 – 2000
    • Elected, American Association for the Advancement of Science, 1996
    • Member, Naval Research Advisory Committee, 1996 - 2000
    • Chairperson, Selection Committee for Bristol-Myers Squibb Award, Outstanding Achievement in Infectious Diseases, 1997 - 1998
    • Member, NCI Board of Scientific Counselors for Basic Science, 1997 – 2001
    • Elected, American Academy of Microbiology – Board of Governors, 1998
    • Elected Fellow, New York Academy of Sciences, 2000
    • Vice Chair, New Jersey State Commission on Cancer Research, 2000 - 2005
    • Member, United States Department of Defense Science Board, 2000 - 2011
    • Member, Scientific Advisory Board, Onconova Therapeutics, Inc, 2001 – date
    • Governor Appointed Chair, New Jersey Commission on Cancer Research, 2005 - 2014
    • Member, AIDS Molecular and Cellular Biology Study Section (AMCB), 2006 - 2010
    • Member, John Scott Award Advisory Committee, 2008 - date
    • Outstanding Women of Science Award, N.J. Assoc. Biomedical Research, 2008
    • American Cancer Society Scientific Research Award, PA Div, 2008
    • Visiting Member, Institute for Advanced Study, Princeton, NJ, 2009 - date
    • Co-Organizer, Centennial Retrovirus Meeting. Prague Czech Republic, 2010
    • Elected Member, AAAS Nominating Committee, Biological Sciences, 2011 - 2014
    • P50 Center Grant Study Section, Washington, DC, 2012
    • Elected Member, Committee on Elections to the American Academy of Microbiology, 2012 - 2016

    Honors & Awards

    • William Procter Prize for Scientific Achievement. Awarded, Sigma Xi (Scientific Research Honor Society), 2018
    • Distinguished Research Award, Center for Retroviral Research, Ohio State University, 2013

    People

    • Richard Katz, PhD
      Research Professor - Collaborator
    • Mark Andrake, PhD
      Assistant Research Professor - Collaborator
    • George Merkel, MS
      Scientific Assistant
    • Katherine Buettner, PhD
      Postdoc Trainee
    • Taryn Serman
      Summer Student Trainee

    Research Interests

    • Molecular aspects of viral replication, focus on human (HIV) and avian (ASLV) retroviruses
    • Structure and function of retroviral integrase
    • Epigenetic control of retroviral gene expression

    Selected Publications

    Skalka, A.M.  Retroviral DNA transposition: Themes and variations. In: Mobile DNA III  (Sandmeyer, S., Craig, N., eds.). ASM Press, in press, 2015. Available in Microbiology http://www.asmscience.org/content/journal/microbiolspec/2/5

    Benleulmi, M.S., Matysiak, J., Henriquez, D.R., Vaillant, C., Lesbats, P., Calmels, C., Naughtin, M., Leon, O., Skalka, A.M., Ruff, M., Lavigne, M., Andreola, M.L., Parissi, V. Intasome architecture and chromatin density modulate retroviral integration into nucleosome. Retrovirology 12:13-29, 2015. PMCID: PMC4358916   http://www.ncbi.nlm.nih.gov/pubmed/25807893

    Haugh, K.A., Shalginskikh, N., Nogusa, S., Skalka, A.M., Katz, R.A., Balachandran, S. The interferon-inducible antiviral protein Daxx is not essential for interferon-mediated protection against avian sarcoma virus. Virol. J. 11:100, 2014. PMCID: PMC4049388   http://www.ncbi.nlm.nih.gov/pubmed/24884573

    Poleshko, A., Kossenkov, A.V., Shalginskikh, N., Pecherskaya, A., Einarson, M.B., Skalka, A.M., Katz, R.A. Human factors and pathways essential for mediating epigenetic gene silencing. Epigenetics 9:1280-1289, 2014. PMCID: PMC4169020  http://www.ncbi.nlm.nih.gov/pubmed/25147916

    Bojja, R.S., Andrake, M.D., Merkel, G., Weigand, S., Dunbrack, R.L., Jr., Skalka, A.M. Architecture and assembly of HIV integrase multimers in the absence of DNA substrates. J. Biol. Chem. 288:7373-7386, 2013. PMCID: PMC3591645   http://www.ncbi.nlm.nih.gov/pubmed/23322775

    Shalginskikh, N., Poleshko, A., Skalka, A.M., Katz, R.A. Retroviral DNA methylation and epigenetic repression are mediated by the antiviral host protein Daxx.  Selected by the Editors as an Article of "Significant Interest". J. Virol. 87:2137-2150, 2013. PMCID: PMC3571491 http://www.ncbi.nlm.nih.gov/pubmed/23221555

    Peletskaya, E., Andrake, M., Gustchina, A., Merkel, G., Alexandratos, J., Zhou, D., Bojja, R.S., Satoh, T., Potapov, M., Kogon, A., Potapov, V., Wlodawer, A., Skalka, A.M. Localization of ASV integrase-DNA contacts by site-directed crosslinking and their structural analysis. PLoS One 6:e27751, 2011. PMCID: PMC3228729     http://www.ncbi.nlm.nih.gov/pubmed/22145019

    Katz, R.A., Merkel, G., Andrake, M.D., Roder, H., Skalka, A.M. Retroviral integrases promote fraying of viral DNA ends. J. Biol. Chem. 286:25710-25718, 2011. PMCID: PMC3138259 http://www.ncbi.nlm.nih.gov/pubmed/21622554

      Bojja, R.S., Andrake, M.D., Weigand, S., Merkel, G., Yarychkivska, O., Henderson, A., Kummerling, M., Skalka, A.M. Architecture of a full-length retroviral integrase monomer and dimer, revealed by small angle X-ray scattering and chemical cross-linking. J. Biol. Chem. 286:17047-17059, 2011. PMCID: PMC3089549   http://www.ncbi.nlm.nih.gov/pubmed/21454648

    Belyi, V.A., Levine, A.J., Skalka, A.M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae are more than 40 to 50 million years old. J. Virol. 84:12458-12462, 2010. PMCID: PMC297638  http://www.ncbi.nlm.nih.gov/pubmed/20861255

     Belyi, V.A., Levine, A.J., Skalka, A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes. PLoS Pathog. 6:e1001030, 2010. PMCID: PMC2912400 http://www.ncbi.nlm.nih.gov/pubmed/20686665

    Poleshko, A., Einarson, M.B., Shalginskikh, N., Zhang, R., Adams, P.D., Skalka, A.M., Katz, R.A. Identification of a functional network of human epigenetic silencing factors. J. Biol. Chem. 285:422-433, 2010. PMCID: PMC2804189    http://www.ncbi.nlm.nih.gov/pubmed/19880521

    Andrake, M.D., Ramcharan, J., Merkel, G., Zhao, X.Z., Burke, T.R., Jr., Skalka, A.M. Comparison of metal-dependent catalysis by HIV-1 and ASV integrase proteins using a new and rapid, moderate throughput assay for joining activity in solution. AIDS Res. Ther. 6:14, 2009. PMCID: PMC2717984      http://www.ncbi.nlm.nih.gov/pubmed/19563676

     Merkel, G., Andrake, M.D., Ramcharan, J., Skalka, A.M. Oligonucleotide-based assays for integrase activity. Methods 47:243-248, 2009. PMCID: PMC2743288 http://www.ncbi.nlm.nih.gov/pubmed/19010419

     Andrake, M.D., Sauter, M.M., Boland, K., Goldstein, A.D., Hussein, M., Skalka, A.M. Nuclear import of Avian Sarcoma Virus integrase is facilitated by host cell factors. Retrovirology 5:73, 2008. PMCID: PMC2527327 http://www.ncbi.nlm.nih.gov/pubmed/18687138

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