Our lab aims to understand cellular host responses to virus infection, and the environment encountered and manipulated by viruses. We study multiple viruses in an integrated experimental approach that combines biochemistry, molecular biology, genetics and cell biology. We have chosen viral models that provide tractable systems to investigate the dynamic interplay between viral genetic material and host defense strategies. The pathways illuminated are key to fighting diseases of both viral infection and genome instability, and our studies have significant implications for the development of efficient viral vectors for gene therapy.
Description of Research:
Viruses try to hijack cellular machinery to aid their own replication, but the host cell often responds with defense systems that can create obstacles for the virus. Watching these battles unfold has contributed significantly to our understanding of fundamental cellular mechanisms and has established viruses as powerful model systems to study cell biology. We have a particular interest in the interactions between viruses and the DNA repair pathways of the host cell. The work in my lab addresses the fundamental question of how the human genome maintains integrity in the face of viral genetic assault. Viral genomes pose a direct threat to the host genome. During infection a battle ensues in which both host and viral genomes must each be protected to maintain their genetic integrity. We study the dynamic interactions between viruses and host cells when their genomes are in conflict. My lab discovered that the cellular apparatus that resolves DNA damage also acts as a defense against viral assault. The sophisticated surveillance network for sensing and repairing DNA prevents an array of human diseases. When compromised it results in genomic instability that ultimately leads to cancer. We are studying how the cellular damage sensing machinery as an intrinsic defense to virus infection, and ways in which viruses mount a counterattack by dismantling the cellular DNA repair machinery or even exploiting it to aid their own replication. In addition to understanding virus-host interactions, studying DNA repair together with the natural process of virus infection provides a platform for interrogating cellular pathways involved in recognition and processing of DNA damage.
We study Adenovirus (Ad), Herpes Simplex Virus (HSV-1), and Adeno-Associated Virus (AAV). These viruses each have different types of DNA genomes and have developed distinct ways of manipulating host defenses. Unraveling the complex host cell response to invading viral genomes has broad implications for fighting diseases of both viral infection and genome instability. Our studies on repair and silencing of viral genomes have significant implications for the development of efficient viral vectors for gene therapy. Viral complexes that manipulate host pathways reveal novel ways in which protein modifications regulate diverse processes. The conflicts between virus and host also impact and inform us about the evolution of our genome.
Virology, Virus Replication, DNA Damage and Repair, Genome Instability, Viral Vectors
We have created an interactive and collaborative lab environment where students and postdocs are encouraged to explore multiple projects and challenge each other intellectually.
- Impact of DNA damage responses on virus infection and gene delivery
- Identifying targets for viral encoded ubiquitin ligases
- Roles for post-translational modifications in regulating viruses
- Epigenetic changes during virus infection
- Identifying host restriction factors during virus infection
- Defining functions for the cellular APOBEC proteins
- Exploiting viral manipulation of cellular pathways to improve gene targeting and gene therapy
Janine D'Souza, Lab Manager
- Associate Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2012– present)
- Ph.D., Molecular Virology, Oxford Polytechnic and the Institute of Virology and Environmental Microbiology of the Natural Environment Research Council (NERC), Oxford, UK (1991)
- B.Sc., Honours degree in Genetics, University of Leeds, UK (1987)
- Chaurushiya, MS, Lilley, CE, Aslanian, A, Meisenhelder, J, Scott, DC, Landry, S, Ticau, S, Boutell, C, Yates,JR, Schulman, BA, Hunter, T and Weitzman, MD. Viral E3 ubiquitin-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain.. Molecular Cell. Vol 46(1) . 2012 Apr:79-90.
- Vogel, R, Seyffert, M, Strasser, R, de Oliveira, AP, Dresch, C, Glauser, DL, Jolinon, A, Salvetti, A, Weitzman,MD, Ackermann, M and Fraefel, C. Adeno-associated virus type 2 modulates the host DNA damage response induced by herpes simplex virus type 1 during co-infection.. Journal of Virology. Vol 86(1) . 2012 Jan:143-155.
- Narvaiza I, Landry S, Weitzman, MD. APOBEC3 proteins and genomic stability: The high cost of a good defense.. Cell Cycle. Vol 11(1) . 2012 Jan:33-8.
- Weitzman MD, Lilley CE, Chaurushiya MS. Changing the ubiquitin landscape during viral manipulation of the DNA damage response.. FEBS Letters. Vol 585(18) . 2011 Sep:2897-906.
- Lilley CE, Chaurushiya MS, Boutell C, Everett RD, Weitzman MD. The Intrinsic Antiviral Defense to Incoming HSV-1 Genomes Includes Specific DNA Repair Proteins and Is Counteracted by the Viral Protein ICP0.. PLoS Pathogens. Vol 7(6) . 2011 Jun:e1002084.
- Landry S, Narvaiza I, Linfesty DC, Weitzman MD. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest.. EMBO Reports. Vol 12(5) . 2011 May:444-50.
- Orazio NI, Naeger CM, Karlseder J, Weitzman MD. The adenovirus E1b55K/E4orf6 complex induces degradation of the Bloom helicase during infection.. Journal of Virology. Vol 85(4) . 2011 Feb:1887-92.
- Weitzman MD, Lilley CE, Chaurushiya MS. Genomes in conflict: maintaining genome integrity during virus infection.. Annual Review of Microbiology. Vol 64. 2010 Oct:61-81.
- Lilley CE, Chaurushiya MS, Boutell C, Landry S, Suh J, Panier S, Everett RD, Stewart GS, Durocher D, Weitzman MD. A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses.. The EMBO Journal. Vol 29(5) . 2010 Mar:943-55.
- Carson CT, Orazio NI, Lee DV, Suh J, Bekker-Jensen S, Araujo FD, Lakdawala SS, Lilley CE, Bartek J, Lukas J, Weitzman MD. Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection.. The EMBO Journal. Vol 28(6) . 2009 Mar:652-62.