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Matthew Weitzman e-mail: weitzman@salk.edu
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Our group studies virus-host interactions and cellular responses to the assault of virus infection. While the virus tries to commandeer the cellular machinery to aid its own replication, the host cell responds with defense systems that create obstacles for the virus. Probing these battles has contributed significantly to our understanding of cellular processes and established viruses as powerful models to study cell biology. The counter defense systems used by viruses reveal insights into fundamental mechanisms and have uncovered cellular targets that are key regulators of the cell. We use three human viruses as model systems to investigate virus-host interactions: Adenovirus (Ad), Herpes Simplex Virus (HSV-1), and Adeno-Associated Virus (AAV). These human DNA viruses are representatives of different viral genomes and lifecycles. We have implemented an integrated experimental approach that combines biochemistry, molecular biology, genetics and cell biology.
Viral infection and replication present the host cell with large amounts of exogenous genetic material and unusual DNA structures. We discovered that viral genomes activate the cellular DNA damage response. We have found examples of where the cellular DNA repair machinery acts as an obstacle to virus infection, and showed that viral oncogenes possess strategies to inactivate repair pathways. Other viruses illustrate how the cellular apparatus can be modified and exploited to aid virus infection. We are interested in the cascade of events activated by viruses and DNA damage, and the mechanisms by which damage sensors and repair apparatus accumulate at sites of damage.
We are also interested in innate intracellular defenses provided by the APOBEC proteins, a family of cytidine deaminases with inhibitory properties against viruses. We discovered that APOBEC3A is a potent inhibitor of parvoviruses such as AAV and of transposition by human LINE-1 elements. Ongoing studies are aimed at understanding the mechanism responsible for viral inhibition and the other cellular functions of APOBEC proteins.
Our work provides mechanistic insights into the recognition of damaged DNA and fundamental lessons in cell biology beyond the field of virology. Understanding how viruses perturb the regulatory pathways that control cell growth and the maintenance of genome integrity reveals lessons about transformation and cancer. In addition to work on virus-host interactions, the lab is also interested in developing viruses into gene delivery systems for gene therapy. This work focuses on harnessing the ability of recombinant viral vectors to deliver genes into cells efficiently and safely.
Examples of viral interactions with DNA damage checkpoint pathways and cell cycle regulators. Effects of the viral proteins (shaded boxes) on their cellular substrates are indicated by the shaded triangles (red indicating interactions that are inhibitory, and green denoting interactions that promote activity of the targeted cellular factors).
Stracker, TH, Carson, CT and Weitzman, MD (2002). Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature, 418, 348- 352.
Carson, CT, Schwartz, RA, Stracker, TH, Lilley, CE, Lee, DV and Weitzman, MD (2003). The Mre11 complex is required for ATM activation and the G2/M checkpoint. EMBO J., 22,6610-6620.
Lilley, CE, Carson, CT, Muotri, AR, Gage, FH and Weitzman, MD (2005). DNA repair proteins affect the HSV-1 lifecycle. Proc. Natl. Acad. Sci. USA, 102, 5844-5849.
Verma IM and Weitzman, MD (2005). Gene Therapy: Twenty-First Century Medicine. Annual Review of Biochemistry 74, 711-738.
Chen, H, Lilley, CE, Yu, Q, Lee, DV, Chou, J, Narvaiza, I, Landau, NR and Weitzman, MD (2006). APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr. Biol. 16, 480-485.
Lilley, CE, Schwartz, RA and Weitzman, MD (2007). Using or Abusing: Viruses and the DNA damage response. Trends in Microbiology 15, 119-126.
Matthew Weitzman received his Ph.D. in Molecular Virology from Oxford Polytechnic and the NERC Institute of Virology in Oxford, England. He conducted postdoctoral work at NIH and also in the Institute for Human Gene Therapy at the University of Pennsylvania.
