# MCV ST activates specific gene transcription by redirecting the activity of the Tip60/p400 complex.

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $33,829

## Abstract

Project Abstract:
 Merkel cell polyomavirus (MCV) is a small DNA tumor virus that causes approximately 80% of Merkel cell
carcinoma (MCC), a highly aggressive skin cancer. Since the discovery of MCV in 2008, it has been shown
that the MCV tumor antigens small T antigen (ST) and large T antigen (LT) are the only viral proteins
consistently expressed in virus-positive MCC cells. Expression of ST alone in Rat1 cells was sufficient to
induce cellular transformation suggesting that ST is the primary driver of cellular transformation in MCC
development. Our lab determined that ST forms a specific complex with L-Myc/MAX and the Tip60/p400
complex (SLT complex) and that a ST mutant incapable of binding to L-Myc and the Tip60/p400 complex
cannot transform cells. The Tip60/p400 complex is a large multi-subunit complex that has lysine
acetyltransferase activity (Tip60 protein) and nucleosome exchange activity (p400 protein). Both of these
activities have been correlated with active gene transcription but further work is necessary to fully understand
the relationship between Tip60/p400 complex activity and gene expression. We hypothesize that MCV ST
redirects the Tip60/p400 complex to L-Myc binding sites to activate a transcriptional program requiring
their lysine acetyltransferase and histone remodeling activity to drive cellular transformation. In Aim 1,
we will assess the effect of ST on Tip60/p400 complex binding and we will compare the direct targets of the
Tip60/p400 complex in control cells with cells expressing ST to determine if ST redirects the complex from
“normal” Tip60/p400 complex binding sites to SLT target gene promoters to activate SLT target gene
transcription. By comparing the list of genes that are direct targets of the SLT complex in normal human cells
to those we previously identified in virus-positive MCC cells, we will generate a list of genes that are
consistently regulated by ST. In Aim 2, we will assess the contribution of Tip60 histone acetyltransferase (HAT)
and p400 nucleosome remodeling activities to ST-mediated gene expression changes and cellular
transformation. In Aim 3, we will adapt the Fkbp/Frb inducible recruitment for epigenetic editing by Cas9 (FIRE-
Cas9) method to the Tip60/p400 complex and then use this system to recruit the Tip60/p400 complex to SLT
target genes in the absence of ST. Upon recruitment, we will measure changes to ST target gene transcription
and the level of Tip60/p400-specific histone marks at SLT target gene promoters. Insights gained from
investigating the ST interaction with L-Myc and the Tip60/p400 complex will provide a deeper
understanding of the oncogenic roles of these factors and understanding the activities of the SLT
complex will lead to identification of improved targeted therapies to combat MCC.

## Key facts

- **NIH application ID:** 10144945
- **Project number:** 5F31CA239345-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Camille Cushman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,829
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144945

## Citation

> US National Institutes of Health, RePORTER application 10144945, MCV ST activates specific gene transcription by redirecting the activity of the Tip60/p400 complex. (5F31CA239345-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10144945. Licensed CC0.

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