Anna Marie Skalka, PhD

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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.

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.
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.
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.
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.
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: 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

Additional Publications

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