Matt Weitzman, Ph.D.
4050 Colket Translational Research Building
The Children’s Hospital of Philadelphia Research Institute
3501 Civic Center Blvd
Philadelphia, PA 19104
Our lab aims to understand host responses to virus infection, and the cellular 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. We have used proteomic approaches to probe the dynamic interactions that take place on viral and cellular genomes during infection, and have uncovered ways that viruses manipulate histones and chromatin as they take control of cellular processes. The pathways illuminated are key to fighting diseases of viral infection, provide insights into fundamental processes that maintain genome instability, and have implications for the development of efficient viral vectors for gene therapy.
Contribution to Science
Work in my lab addresses the dynamic interactions between viruses and host cells when their genomes are in conflict. My lab pioneered the study of cellular damage sensing machinery as an intrinsic defense to virus infection. We have studied the DNA damage responses with a range of human DNA viruses and identified distinct ways that they manipulate signaling networks and DNA repair processes. Studying DNA damage as part of the cellular response to infection has opened up a new area in the biology of virus-host interactions. It has also provided a platform for interrogating cellular pathways involved in recognition and processing of DNA damage. This work revealed that the MRN complex is the mammalian sensor of DNA breaks and viral genomes, and that it is required for efficient activation of ATM/ATR damage signaling.
- 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.
- Lilley, CE, Chaurushiya, MS, Boutell, C, Everett, RD, and Weitzman, MD (2011). The intrinsic antiviral defense to incoming HSV-1 genomes includes specific DNA repair proteins and is counteracted by the viral protein ICP0. PLoS Pathog 7:e1002084. PMC3116817
- 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 (2012). Viral E3 ubiquitin-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain. Mol Cell 46, 79-90. PMC3648639
I have had a long-standing interest in viral and host proteins that bind DNA and chromatin. As a postdoc I used biochemical approaches to identify a recognition sequence for the Rep protein of AAV within the site-specific integration site on chromosome 19 (AAVS1). I demonstrated that Rep proteins can mediate interaction between cellular and viral DNA to promote targeted integration. We have recently employed proteomic approaches to identify proteins associated with viral DNA genomes during infection, as well as the modifications that occur to chromatin on the host genome. We have analyzed histone post-translational modifications during virus infection and shown how these are altered by viruses. We recently discovered that the histone-like protein VII encoded by Adenovirus for packaging of its genome, can also affect the composition of cellular chromatin by retaining danger signals to overcome immune signaling. We are now interested in looking at how viruses impact genome and nuclear architecture and the effects this has on gene expression.
- Weitzman, MD, Kyöstiö, SRM, Kotin, RM and Owens, RA (1994). Rep proteins of adeno-associated virus (AAV) mediate a complex formation between AAV DNA and the AAV integration site on human chromosome 19. Proc Natl Acad Sci USA, 91, 5808-5812.
- Kulej, K, Avgousti, DC, Weitzman, MD and Garcia, BA (2015). Characterization of histone post-translational modifications during virus infection using mass spectrometry-based proteomics. Methods 90, 8-20.
- Avgousti, DC, Herrmann, C, Sekulic, N, Kulej, K, Petrescu, J, Molden, RC, Pancholi, NJ, Reyes, ED, Seeholzer, SH, Black, BE, Garcia, BA and Weitzman, MD (2016). A core viral protein binds host nucleosomes to sequester immune danger signals. Nature 535, 173-177. PMC4950998
- Kulej, K, Avgousti, DC, Sidoli, S, Herrman C, Della Fera, AN, Kim ET, Garcia, BA and Weitzman, MD (2017). Time-resolved global and chromatin proteomics during Herpes Simplex Virus Type 1 (HSV-1) infection. Mol Cell Proteomics 16, S92-S107.
- Reyes, RD, Kulej, K, Akhtar, LN, Avgousti, DC, Pancholi, NJ, Kim, ET, Bricker, D, Koniski, S, Seeholzer, SH, Isaacs, SN, Garcia, BA, and Weitzman, MD. Identifying host factors associated with DNA replicated during virus infection. (in press).
My lab is interested in cellular responses that restrict virus replication. APOBEC3 proteins belong to a family of cytidine deaminases that provide a line of defense against retroviruses and endogenous mobile retroelements. We were the first to show that human APOBEC3A (A3A) is a catalytically active cytidine deaminase, with a preference for ssDNA. We demonstrated that A3A is a potent inhibitor of endogenous retroelements such as LINE1, and also blocks replication of single-stranded parvoviruses such as AAV and MVM. We have also shown how the SAMHD1 protein limits replication of the DNA virus HSV-1. We discovered ways that cellular DNA repair proteins can act as species-specific barriers through their interaction with viral proteins.
- 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 Bio 16, 480-485.
- Narvaiza, I, Linfesty, DC, Greener, BN, Hakata, Y, Pintel, DJ, Logue, E, Landau, NR, and Weitzman, MD (2009). Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathog 5, e1000439. PMC2678267
- Richardson, SR, Narvaiza, I, Planegger, RA, Weitzman, MD and Moran, JV (2014). APOBEC3A deaminates transiently exposed single-strand DNA that arises during LINE-1 retrotransposition. eLife 3, e02008. PMC4003774
- Kim, ET, White, TE, Brandariz-Nunez, A, Diaz-Griffero, F, and Weitzman, MD (2013). SAMHD1 restricts herpes simplex virus type 1 (HSV-1) in macrophages by limiting DNA replication. J Virol 87, 12949-12956. PMC3838123
- Lou, DI, Kim, ET, Shan, S, Meyerson, NR, Pancholi, NJ, Mohni, KM, Enard, D, Petrov, DA, Weller, SK, Weitzman, MD*, and Sawyer, SL (2016). An intrinsically disordered region of the DNA repair protein Nbs1 is a species-specific barrier to Herpes Simplex Virus 1 in primates. Cell Host & Microbe 20, 178-188. (*Co-corresponding author)
Proteins that mutate viral genetic material must also be carefully regulated to prevent deleterious effects on the host genome. While studying antiviral functions for A3A we discovered that the enzyme can also act on the cellular genome, inducing DNA breaks and cell cycle arrest. We suggested therefore that APOBEC proteins cause genomic instability and contribute to malignancy, and we are now studying how they are regulated to prevent inappropriate mutations. This body of work demonstrates how studying virus-host interactions can lead to insights into fundamental processes that impact cellular genomic integrity. We have recently found A3A upregulated in a subset of human leukemias and demonstrated how this provides vulnerability for targeted cancer therapies.
- Landry, S, Narvaiza, I, Linfesty, DC and Weitzman, MD (2011). APOBEC3A can activate the DNA damage response and cause cell cycle arrest. EMBO Reports 12, 444-450. PMC3090015
- Narvaiza, I, Landry, S, and Weitzman, MD (2012). APOBEC3 proteins and genome stability: The high cost of a good defense? Invited Extraview in Cell Cycle 11, 33-38.
- Green, AM, Landry, S, Budagyan, K, Avgousti, D, Shalhout, S, Bhagwat, AS and Weitzman, MD (2016). APOBEC3A damages the cellular genome during DNA replication. Cell Cycle 15, 998-1008. PMC4889253
- Green, AM, Budagyan, K, Hayer, KE, Reed, MA, Savani, MR, Wertheim, GB and Weitzman, MD (2017). Cytosine deaminase APOBEC3A sensitizes leukemia cells to inhibition of the DNA replication checkpoint. Cancer Research (in press)
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