# Role of histone kinase VprBP in gene silencing: mechanisms, targets, and regulation

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $377,438

## Abstract

PROJECT SUMMARY
The proper regulation of gene expression in human cells is achieved by signals emanating from a distinct
histone modification occurring in chromatin architecture. Studies of gene regulation mechanisms by histone
modification may thus aid in the understanding and treatment of ailments caused by abnormal transcription
regulation. VprBP is a nuclear protein that was originally identified on the basis of its ability to interact with
HIV-1 viral protein R. Although VprBP has been studied mainly in connection with Cul4 E3 ubiquitin ligase
activity, we recently discovered that VprBP is a transdominant inhibitor of the p53 tumor suppressor and
counteracts p53 transactivation, apoptosis, and growth suppression functions. High-level expression of
VprBP in a wide range of human tumor samples and cancer cell lines, but low to undetectable expression
of VprBP in their normal counterparts, suggests that VprBP possesses oncogenic properties. Our finding
that VprBP-depleted cancer cells grow very slow and do not produce tumor xenografts also supports the
idea that VprBP facilitates tumorigenesis. Our studies indicated that VprBP interacts with histone H3 tails
protruding from nucleosomes and that this interaction facilitates VprBP recruitment and subsequent gene
silencing in cancer cells. Unexpectedly, more recent work from our laboratory uncovered the presence of
kinase activity specific for threonine 120 (T120) of histone H2A in VprBP. Our functional studies
demonstrated that H2A-T120 phosphorylation (H2A-T120p) is essential for VprBP-driven gene silencing in
cancer cells. Based on the available evidence, VprBP is the only kinase that is responsible for H2A-T120p
occurring in human cancer cells. Importantly, our development of a highly selective inhibitor to manipulate
the oncogenic VprBP kinase activity sets the stage for a more detailed analysis of VprBP function in
abnormal gene silencing in cancer cells.
The long-term goal of the proposed research is to understand the biological processes that VprBP controls
and the molecular basis of its action as a mediator of tumorigenesis. The overall objectives are to
determine the mechanisms of VprBP-mediated inactivation of the genes that regulate cell proliferation and
to develop a set of molecular tools for controlling the magnitude of H2A-T120p at VprBP target loci in a
precise manner. Our hypothesis is that VprBP establishes and maintains the silent state of key growth
regulatory genes by a two-step mechanism wherein it is recruited to target genes via interaction with gene-
specific transcription factors, and phosphorylates H2A-T120 as a mark for the recruitment of additional
factors involved in gene repression and cell transformation. In the first Aim, we will employ the RNA-guided
CRISPR-Cas9 system in which we can manipulate H2A-T120p at specific loci, and identify the genes that
are directly regulated by VprBP-mediated H2AT-120p and critical for VprBP-promoted oncogenic events. In
the second...

## Key facts

- **NIH application ID:** 9939477
- **Project number:** 5R01CA201561-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** WOOJIN AN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,438
- **Award type:** 5
- **Project period:** 2016-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939477

## Citation

> US National Institutes of Health, RePORTER application 9939477, Role of histone kinase VprBP in gene silencing: mechanisms, targets, and regulation (5R01CA201561-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939477. Licensed CC0.

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