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Berrios, Christian Jose

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Berrios

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Christian Jose

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Berrios, Christian Jose
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    Simian Virus 40 and Human Polyomavirus Oncogenic Perturbations
    (2016-07-25) Berrios, Christian Jose; Dyson, Nicholas; Gewurz, Benjamin; Toker, Alex; Schaffhausen, Brian
    Polyomaviruses have widespread prevalence across many animal species. Polyomaviruses are small DNA tumor viruses that endow their host cells with proliferative signals through interactions between their small T (ST) and large T (LT) antigens and host cell proteins. For example, simian virus 40 (SV40) LT can simultaneously bind and inhibit the retinoblastoma (pRb) and p53 tumor suppressor pathways, while ST binds to and perturbs protein phosphatase 2A (PP2A). In this dissertation, we sought to characterize the oncogenic properties of T antigens from several polyomaviruses, including Malawi polyomavirus (MWPyV), Merkel cell polyomavirus (MCPyV) and SV40, and determine whether they had shared or unique growth-promoting mechanisms. MWPyV is a recently identified human polyomavirus with unknown transforming potential. We found that its T antigens, although capable of binding to pRb, p53 and PP2A, were not as transforming as T antigens from SV40. In contrast, Merkel cell polyomavirus (MCPyV) ST is required for maintenance of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. To gain insights into its transforming function, we performed transcriptome profiling of normal human cells expressing MCPyV ST and identified significant perturbations in glycolysis-related genes. Furthermore, targeting aerobic glycolysis inhibited MCPyV-induced transformation as well as MCC growth. To gain further insight into MCPyV virus-host interactions in a relevant cell type, we pursued the development of a system to isolate and characterize primary Merkel cells and investigate their response to MCPyV T antigens. Co-expression of SV40 ST and LT together with the telomerase catalytic subunit (hTERT) and oncogenic Ras is sufficient to fully transform normal human fibroblasts. SV40 ST is known to bind to the A and C subunits of PP2A, displacing B subunits and altering PP2A-mediated regulation of numerous cancer-associated pathways. We were interested in pursuing SV40 STs recently described association with a PP2A A, B and C subunit-containing complex known as the striatin-interacting phosphatase and kinase (STRIPAK) complex. We determined that the STRIPAK complex was required for SV40 STs transforming ability and this was due, at least in part, to inhibition of the STRIPAK associated-MAP4K4 kinase activity. The results presented in this dissertation highlight the striking distinctions in the transforming mechanisms of three divergent polyomaviruses. While each polyomavirus targets some of the same cancer pathways such as pRb, full transformation is achieved through non-overlapping mechanisms specific to each virus. Such an analysis of the polyomavirus tumor virus family provides insight into the heterogeneity of their oncogenic activity, thereby facilitating the discovery of novel cancer targets and therapeutic opportunities.
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    Identification of FAM111A as an SV40 Host Range Restriction and Adenovirus Helper Factor
    (Public Library of Science, 2012) Fine, Debrah A.; Rozenblatt-Rosen, Orit; Padi, Megha; Korkhin, Anna; James, Robert L.; Adelmant, Guillaume; Yoon, Rosa; Guo, Luxuan; Berrios, Christian Jose; Zhang, Ying; Calderwood, Michael; Velmurgan, Soundarapandian; Cheng, Jingwei; Marto, Jarrod; Hill, David; Cusick, Michael; Vidal, Marc; Florens, Laurence; Washburn, Michael P.; Litovchick, Larisa; DeCaprio, James
    The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.