PEOPLE

Matthew D. Weitzman, PhD

Associate Professor of Microbiology, Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine

Contact Information4050 Colket Translational Research Building
The Children's Hospital of Philadelphia Research Institute
3501 Civic Center Blvd
Philadelphia, PA 19104
Office: 267-425-2068

Email: weitzmanm@email.chop.edu

Specialty Division

Immunobiology and Experimental Pathology

Research Expertise

Research Interests:
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.

Keywords:
Virology, Virus Replication, DNA Damage and Repair, Genome Instability, Viral Vectors

Current projects:
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

Lab Personnel

 

Graduate Groups

Cell and Molecular Biology

Education

B.Sc. (Honours degree in Genetics), University of Leeds, UK, 1987
Ph.D. (Molecular Virology), Oxford Polytechnic and the Institute of Virology and Environmental Microbiology of the Natural Environment Research Council (NERC), Oxford, UK, 1991

Specialty Certification

Postgraduate Training

Fogarty Postdoctoral Fellow, Laboratory of Molecular and Cellular Biology, NIDDK, NIH, 1991-1993
Postdoctoral Fellow, Cystic Fibrosis Foundation Fellow, University of Pennsylvania Medical Center, 1993-1994

Awards and Honors

Natural Environment Research Council (NERC) Graduate Student Scholarship, 1984-1987
Prize Winner in the Daily Telegraph Young Science Writer Awards, "Kamikaze Caterpillar Killers", 1989
Fogarty Visiting Fellowship at NIH, 1991-1993
Cystic Fibrosis Foundation Postdoctoral Fellowship, 1994-1995
Innovation Grant recipient, Presidents' Club of the Salk Institute, 1998
Innovation Grant recipient, Presidents' Club of the Salk Institute, 1999
Young Investigator Award, American Society for Gene Therapy, 2004
Innovation Grant recipient, the Salk Institute Innovation Fund, 2008
Pioneer Developmental Chair, Salk Institute, 2008-2011
Harold S Ginsberg Lecture, America Society for Virology Annual Meeting, 2010
Foerderer Award, The Children’s Hospital of Philadelphia, 2013
CHOP Faculty Mentor Award, The Children's Hospital of Philadelphia, 2016
CHOP Award for Excellence in Mentoring Research Trainees, The Children's Hospital of Philadelphia, 2017

Memberships and Professional Organizations

American Society for Virology (ASV), 1990 - Present
American Society for Microbiology (ASM), 1990 - Present
American Society for Gene and Cell Therapy (ASGCT), 1990 - Present
University of Pennsylvania, 1997 - Present
National Gene Vector Labs (NGVL), 1999 - 2006
United States-Israel Binational Science Foundation, 2000 - 2000
Wellcome Trust Foundation, UK, 2001 - Present
Italian Telephon Foundation, 2002 - 2002
American Society for Gene and Cell Therapy (ASGCT), 2002 - Present
NIH Molecular Therapy Core Centers, 2003 - 2003
NIH Special Emphasis Panel on Gene Delivery, 2003 - 2003
International Centre for Genetic Engineering and Biotechnology
(ICGEB), Trieste, Italy, 2004 - 2004
NIH Virology A Study Section, 2004 - 2004
Philip Morris External Research Program, 2004 - 2004
Alliance for Cancer Gene Therapy, 2005 - 2005
NIH Special Emphasis Panel for Gene Therapy PO1 Grants, 2005 - 2005
Medical Research Council (MRC), UK, 2005 - Present
NIH Special Emphasis Panel for SBIR grant, 2005 - 2005
Human Frontiers Science Program, 2006 - Present
University of Washington, Molecular Therapy Core Center, 2006 - 2006
NIH Virology A Study Section, 2006 - 2008
NIH Atherosclerosis & Inflammation Study Section, 2006 - 2006
Loyola University, Microbiology & Immunology, Chicago, 2008 - 2008
Association Française contre les Myopathies, France, 2009 - 2010
NIH Special Emphasis Panel for Virology, 2009 - 2009
Northwest Genome Engineering Consortium, Seattle, 2009 - 2009
Israel Science Foundation (ISF), 2009 - Present
Control of Infectious Diseases Research Fund, Hong Kong, 2009 - 2009
NIH Virology B Study Section, 2010 - 2010
Cancer Prevention and Research Institute of Texas (CPRIT), 2010 - Present
Swiss National Science Foundation, 2010 - 2010
The National Medical Research Council of Singapore, 2010 - 2010
Italian Association for Cancer Research (AIRC), 2011 - Present
University of Kansas Medical Center (KUMC) Grant Program, 2012 - 2012
Health and Medical Research Fund (HMRF), Hong Kong, 2012 - Present
National Institutes of Health, National Institute of Dental and Craniofacial Research, Special Grants Review Panel, 2013 - 2013
“Fondation pour la Recherche Médicale” (FRM), 2013 - 2013
National Science Center, Poland, 2013 - 2013
National Institutes of Health, National Cancer Institute, 2013 - Present
The Children's Hospital of Philadelphia, 2014 - Present
National Institutes of Health, Cancer Etiology (CE) Study Section, 2015 - 2015
German-Israel Foundation for Scientific Research and Development, 2015 - Present
Program Committee, American Society of Virology, 2015 - 2017
Fight for Sight Foundation, United Kingdom, 2016 - 2016
Austrian Science Foundation, 2016 - 2016
National Institutes of Health, Virology B (VIRB) Study Section, 2016 - 2016
National Institutes of Health, Cancer Etiology (CE) Study Section, 2016 - Present
Israel Cancer Research Fund (ICRF), 2017 - 2020

Selected Publications

Viral E3 ubiquitin-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain.

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, Molecular Cell 46(1): 79-90, 2012

Adeno-associated virus type 2 modulates the host DNA damage response induced by herpes simplex virus type 1 during co-infection.

Vogel, R, Seyffert, M, Strasser, R, de Oliveira, AP, Dresch, C, Glauser, DL, Jolinon, A, Salvetti, A, Weitzman,MD, Ackermann, M and Fraefel, C, Journal of Virology 86(1): 143-155, 2012

APOBEC3 proteins and genomic stability: The high cost of a good defense.

Narvaiza I, Landry S, Weitzman, MD, Cell Cycle 11(1): 33-8, 2012, PMID:22157092

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Changing the ubiquitin landscape during viral manipulation of the DNA damage response.

Weitzman MD, Lilley CE, Chaurushiya MS, FEBS Letters 585(18): 2897-906, 2011, PMID:21549706

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The Intrinsic Antiviral Defense to Incoming HSV-1 Genomes Includes Specific DNA Repair Proteins and Is Counteracted by the Viral Protein ICP0.

Lilley CE, Chaurushiya MS, Boutell C, Everett RD, Weitzman MD, PLoS Pathogens 7(6): e1002084, 2011, PMID:21698222

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APOBEC3A can activate the DNA damage response and cause cell-cycle arrest.

Landry S, Narvaiza I, Linfesty DC, Weitzman MD, EMBO Reports 12(5): 444-50, 2011, PMID:21460793

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The adenovirus E1b55K/E4orf6 complex induces degradation of the Bloom helicase during infection.

Orazio NI, Naeger CM, Karlseder J, Weitzman MD, Journal of Virology 85(4): 1887-92, 2011, PMID:21123383

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Genomes in conflict: maintaining genome integrity during virus infection.

Weitzman MD, Lilley CE, Chaurushiya MS, Annual Review of Microbiology 64(): 61-81, 2010, PMID:20690823

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A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses.

Lilley CE, Chaurushiya MS, Boutell C, Landry S, Suh J, Panier S, Everett RD, Stewart GS, Durocher D, Weitzman MD, The EMBO Journal 29(5): 943-55, 2010, PMID:20075863

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Mislocalization of the MRN complex prevents ATR signaling during adenovirus infection.

Carson CT, Orazio NI, Lee DV, Suh J, Bekker-Jensen S, Araujo FD, Lakdawala SS, Lilley CE, Bartek J, Lukas J, Weitzman MD, The EMBO Journal 28(6): 652-62, 2009, PMID:19197236

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