Reciprocal translocation of the PML tumor suppressor gene and retinoic acid receptor alpha gene is found in nearly all cases of human acute promyelocytic leukemia (APL). The PML-RAR-alpha fusion protein lacks PML tumor suppressor activity and blocks RAR-alpha-induced myeloid cell differentiation, resulting in the cancerous expansion of myeloid cell precursors. Normally, the PML protein is localized within discrete nuclear structures referred to as PML nuclear bodies, PML oncogenic domains (PODs), or ND10. PODs are disrupted in the nuclei of leukemic cells from patients with APL. During disease remission, normal POD structures reform. These results, and others, indicate that deregulation of PML activity may be linked to a variety of human malignancies. PODs are dynamic structures, and the PML protein has been implicated in a variety of important cellular processes including transcriptional regulation, cellular growth control, repair of DNA damage, apoptosis, and response to interferon. PML nuclear bodies are targets of DNA viruses. The adenovirus (Ad) E4 ORF3 protein is necessary and sufficient to mediate the reorganization of PML nuclear bodies, and associated components, into track-like structures early during viral infection. Ad E4 ORF3 also directs the relocalization of nuclear proteins involved in a cellular DNA damage response to Ad infection including Mre11, RadSO and Nbs1 (the MRN complex). E4 ORF3 inhibits MRN activity to block DNA repair pathways that interfere with Ad DNA replication. The E4 ORF3 protein directly binds to and relocalizes the transcriptional regulator TIF1 alpha. The functional consequences of TIF1 alpha interaction with E4 ORF3 are unknown, but may influence viral and/or cellular gene expression, or the ability of E4 ORF3 to reorganize PML or MRN proteins during viral infection. Finally, we have shown that Ad E4 ORF3 abrogates an interferon response during viral infection and this function may involve PML. Our goals are to understand how the different functions of the Ad E4 ORF3 protein may be related to each other and the underlying mechanisms of E4 ORF3 protein activity. The elucidation of Ad E4 ORF3 functions is expected to provide unique insight into the function of PML oncogenic domains, whose deregulation are linked to the development of human cancers, as well as the regulation of different cellular effectors and cellular responses during viral infection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122677-03
Application #
7579153
Study Section
Virology - A Study Section (VIRA)
Program Officer
Daschner, Phillip J
Project Start
2007-05-01
Project End
2012-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
3
Fiscal Year
2009
Total Cost
$327,472
Indirect Cost
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Zheng, Yueting; Stamminger, Thomas; Hearing, Patrick (2016) E2F/Rb Family Proteins Mediate Interferon Induced Repression of Adenovirus Immediate Early Transcription to Promote Persistent Viral Infection. PLoS Pathog 12:e1005415
Avgousti, Daphne C; Herrmann, Christin; Kulej, Katarzyna et al. (2016) A core viral protein binds host nucleosomes to sequester immune danger signals. Nature 535:173-7
Sohn, Sook-Young; Hearing, Patrick (2016) The adenovirus E4-ORF3 protein functions as a SUMO E3 ligase for TIF-1? sumoylation and poly-SUMO chain elongation. Proc Natl Acad Sci U S A 113:6725-30
Sohn, Sook-Young; Hearing, Patrick (2016) Adenovirus Early Proteins and Host Sumoylation. MBio 7:
Bridges, Rebecca G; Sohn, Sook-Young; Wright, Jordan et al. (2016) The Adenovirus E4-ORF3 Protein Stimulates SUMOylation of General Transcription Factor TFII-I to Direct Proteasomal Degradation. MBio 7:e02184-15
Sohn, Sook-Young; Bridges, Rebecca G; Hearing, Patrick (2015) Proteomic analysis of ubiquitin-like posttranslational modifications induced by the adenovirus E4-ORF3 protein. J Virol 89:1744-55
Vink, Elizabeth I; Zheng, Yueting; Yeasmin, Rukhsana et al. (2015) Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression. Viruses 7:2428-49
Sohn, Sook-Young; Hearing, Patrick (2012) Adenovirus regulates sumoylation of Mre11-Rad50-Nbs1 components through a paralog-specific mechanism. J Virol 86:9656-65
Vink, Elizabeth I; Yondola, Mark A; Wu, Kai et al. (2012) Adenovirus E4-ORF3-dependent relocalization of TIF1ýý and TIF1ýý relies on access to the Coiled-Coil motif. Virology 422:317-25
Patsalo, Vadim; Yondola, Mark A; Luan, Bowu et al. (2012) Biophysical and functional analyses suggest that adenovirus E4-ORF3 protein requires higher-order multimerization to function against promyelocytic leukemia protein nuclear bodies. J Biol Chem 287:22573-83

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