# Deciphering the molecular mechanisms of histone code recognition by ATAD2/B

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $90,838

## Abstract

ATAD2 is an important co-activator of the estrogen and androgen receptors2,4. ATAD2 is known to be up-
regulated in multiple different types of cancer including breast, lung, gastric, endometrial, renal, and
prostate5,7,9-12. Up-regulation of ATAD2 is often correlated with poor patient outcomes, and can be used as
prognostic marker9,12-14. Furthermore, silencing the expression of ATAD2 through RNA interference inhibits cell
proliferation and promotes apoptosis in ovarian carcinoma, and inhibits migration and invasion of
hepatocellular carcinoma and colorectal cancer cells13,15,16. ATAD2B, is a poorly studied paralog of the ATAD2
gene, and although ATAD2 and ATAD2B are highly conserved, there is little known about the function of
ATAD2B or its role in oncogenesis. Both the ATAD2/B proteins contain two conserved domains: an AAA
ATPase domain and a bromodomain6. The overall objective of the proposed research is to determine how di-
acetyllysine recognition by the ATAD2/B bromodomains regulates the cellular function of these proteins. This
proposal aims to: (1) characterize how cross-talk between histone modifications modulate acetyllysine
recognition by the ATAD2/B bromodomains; (2) outline the molecular mechanism(s) of di-acetylated histone
recognition by the ATAD2/B bromodomains; (3) determine the functional significance of di-acetyllysine
recognition by the ATAD2/B bromodomains. A unique combination of in vitro biochemical, biophysical, and
structural biology studies on the ATAD2/B bromodomains will be coupled with in vivo functional genomic
investigations using a breast cancer progression model to characterize the biological roles of the ATAD2/B
bromodomains. We will evaluate the impact of neighboring histone modifications on histone H4 tail recognition
using peptide array assays in combination with isothermal titration calorimetry (ITC) and nuclear magnetic
resonance (NMR) chemical shift perturbation techniques. The atomic resolution structures of the ATAD2/B
bromodomains bound to their di-acetylated histone tail ligands will be solved by NMR or X-ray crystallography.
To characterize the binding mode of the ATAD2/B bromodomains with their histone ligands we will carry out
analytical ultracentrifugation, size-exclusion chromatography, ITC, and NMR T1/T2 relaxation experiments.
Site-directed mutagenesis coupled with NMR and ITC will be used to measure the effects on ligand binding,
and identify differences in the binding pockets of the ATAD2/B bromodomains. We will compare the genome-
wide associations of ATAD2/B with histone H4 acetylation patterns in a breast cancer progression model to
determine the impact of ATAD2/B on breast cancer cell phenotypes using ChIP-seq and RNA-seq, followed by
cellular migration and invasion assays. Our multi-faceted approach will correlate specific histone modifications
with ATAD2/B binding and action, which will allow us to connect histone H4 acetylation marks to bromodomain
function in cancer cell proliferation....

## Key facts

- **NIH application ID:** 10410677
- **Project number:** 3R01GM129338-04S1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Seth E Frietze
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $90,838
- **Award type:** 3
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410677

## Citation

> US National Institutes of Health, RePORTER application 10410677, Deciphering the molecular mechanisms of histone code recognition by ATAD2/B (3R01GM129338-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10410677. Licensed CC0.

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