# Mechanism of histone H2A.Z exchange catalyzed by SWR1 chromatin remodeler

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $590,600

## Abstract

DNA in the genome is compacted with histone proteins as nucleosomes, fundamental
organizational units of chromosomes in the cell nucleus. Nucleosomes are arrayed in fibers of
chromatin, associated with nonhistone regulators, architectural proteins and RNA in the cell
nucleus. The architecture of chromatin has an important role in the regulation of gene expression
in the life of a cell. This project aims to investigate the very large, 14-component, chromatin
remodeling protein complex called SWR1 in the budding yeast model organism. SWR1 is
evolutionarily conserved from yeast to humans, and functions as an enzyme to catalyze exchange
of the minor histone variant H2A.Z for canonical histone H2A, the bulk histone species in cells.
H2A.Z specifically marks nucleosomes next to nucleosome-deficient promoter and enhancer
elements, modulating recruitment and activity of the RNA polymerase machinery. The dysfunction
of SWR1 and H2A.Z are implicated in disease, including cancer.
The molecular mechanism of the H2A.Z exchange reaction is not well understood. The proposed
work will systematically extend biochemical studies of purified, SWR1 mutant complexes deficient
for individual components or specific domains. We will use established biochemical assays and
a high-throughput fluorescence resonance energy transfer assay that quantifies the rate of
histone exchange. We will develop a single-molecule imaging platform to detect specific reaction
intermediates and measure their lifetimes during histone exchange. Detection of biochemical
defects in SWR1 mutants will inform the roles of the corresponding normal components in the
H2A.Z exchange pathway. In collaboration with accomplished structural biologists working at
moderate and high resolution, we plan to gain high-resolution structural information on the SWR1
enzyme complex, free and bound to substrates, to increase knowledge of the structural basis of
histone exchange, and assist future rational drug design and drug screening.

## Key facts

- **NIH application ID:** 9840914
- **Project number:** 5R01GM125831-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Carl Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $590,600
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840914

## Citation

> US National Institutes of Health, RePORTER application 9840914, Mechanism of histone H2A.Z exchange catalyzed by SWR1 chromatin remodeler (5R01GM125831-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9840914. Licensed CC0.

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