This project addresses the role of host cell factor-1 (HCF-1) in regulating the herpes simplex virus (HSV) life cycle. HSV is an important human pathogen responsible for a spectrum of diseases including painful lesions, corneal scarring and life-threatening encephalitis. Productive or lytic infection in epithelial cells is initiated by the viral transcription factor VP16, which is released from the virion into the cytosol. There VP16 binds HCF- 1, translocates to the nucleus and together activates the HSV immediate-early (IE) genes. HSV also colonizes sensory neurons where it can establish latency, re-emerging as periodic episodes of localized lytic replication. In spite of extensive analyses, the molecular roadblocks preventing lytic replication in latent neurons remain elusive. Insufficient IE gene expression is likely to be an important contributing factor. HCF-1 is found in the nucleus of most cells, acting as an essential transcriptional cofactor for cell proliferation and cytokinesis. In neurons, however, HCF-1 is cytoplasmic but moves to the nucleus in response to DNA-damaging agents, toxins or mechanical stress. The same stimuli induce latent HSV to re-enter lytic replication, implying a causal relationship between HCF-1 localization and HSV lytic replication. This proposal investigates mechanisms that control localization and function of HCF-1 in different regions of the nucleus. We focus on HPIP and Brd7, two cellular proteins that bind to conserved domains of HCF-1. HPIP is a shuttle factor that exports HCF-1 from the nucleus to the cytosol. Our studies show that HPIP is found in both cytosol and mitochondrial and in Aim 1 we will examine the signals that allow HPIP to partition between these cytoplasmic compartments and more precisely define the localization within mitochondria. Brd7 is a chromatin-binding bromodomain protein and ectopic expression causes major changes in nucleolar structure, leading to stabilization of the stress-sensor p53 and incorporation of HCF-1 in novel nucleolar structures. Similar alterations occur when cells sustain DNA double-strand breaks and we hypothesize that HCF-1 and Brd7 are key players in the response to genomic insults.
Aim 2 investigates the molecular mechanisms by which Brd7 and HCF-1 initiate nucleolar breakdown and Aim 3 addresses the physiological consequences with regard to cell cycle, rRNA transcription and HSV lytic replication. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM061139-06A1
Application #
7097516
Study Section
Virology - A Study Section (VIRA)
Program Officer
Carter, Anthony D
Project Start
2001-03-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$338,655
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kim, Ju Youn; Mandarino, Angelo; Chao, Moses V et al. (2012) Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons. PLoS Pathog 8:e1002540
Wilson, Angus C; Mohr, Ian (2012) A cultured affair: HSV latency and reactivation in neurons. Trends Microbiol 20:604-11
Kobayashi, Mariko; Wilson, Angus C; Chao, Moses V et al. (2012) Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor. Genes Dev 26:1527-32
Kobayashi, Mariko; Kim, Ju-Youn; Camarena, Vladimir et al. (2012) A primary neuron culture system for the study of herpes simplex virus latency and reactivation. J Vis Exp :
Xi, Xiangmei; Persson, Linda M; O'Brien, Michael W et al. (2012) Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters. J Virol 86:1021-33
Persson, Linda M; Wilson, Angus C (2010) Wide-scale use of Notch signaling factor CSL/RBP-Jkappa in RTA-mediated activation of Kaposi's sarcoma-associated herpesvirus lytic genes. J Virol 84:1334-47
Camarena, Vladimir; Kobayashi, Mariko; Kim, Ju Youn et al. (2010) Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. Cell Host Microbe 8:320-30
Misaghi, Shahram; Ottosen, Søren; Izrael-Tomasevic, Anita et al. (2009) Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol 29:2181-92
Pearce, Michael; Matsumura, Satoko; Wilson, Angus C (2005) Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi's sarcoma-associated herpesvirus originate from a common promoter. J Virol 79:14457-64
Wong, Lai-Yee; Wilson, Angus C (2005) Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induces a strong bend on binding to terminal repeat DNA. J Virol 79:13829-36

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