# Understanding the function of histone H3 as an oxidoreductase enzyme

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $452,299

## Abstract

PROJECT SUMMARY
 This application proposes to investigate the newly discovered function of histone H3 as an oxidoreductase
enzyme, catalyzing the reduction of cupric (Cu+2) ions to the biousable cuprous (Cu+1) form. The eukaryotic
histone H3-H4 tetramer contains a putative Cu2+ binding site at the interface of the apposing H3 proteins with
unknown function. The coincident emergence of eukaryotes with global oxygenation, which challenged cellular
copper utilization, raised the possibility that histones may function in cellular copper homeostasis. We have
extensive evidence that histones are required for efficient use of copper inside cells, which depend on availability
of copper ions in their reduced, +1 oxidation state. It is the Cu+1 ions that are trafficked intracellularly by protein
chaperones to destination target proteins. We show that the H3-H4 tetramer, assembled from recombinant
histones, binds Cu2+ and catalyzes its reduction to Cu1+ in vitro. Loss- and gain-of-function mutations of the
putative active site residues correspondingly altered copper binding and the enzymatic activity, as well as
intracellular Cu1+ levels and copper-dependent activities such as mitochondrial respiration and superoxide
dismutase 1 (Sod1) function in S. cerevisiae. Our data have uncovered a function of the histone H3-H4 tetramer
with little precedence in literature, revealing that the eukaryotic genome is wrapped around an enzyme. We now
propose to develop a mechanistic understanding of this new function of histones and how it is regulated and
linked to cellular copper homeostasis. In Aim 1, we seek to understand the mechanism of catalysis by
determining the structure of copper-bound H3-H4 tetramer and the contributions of the residues in and around
the active site. In Aim 2, we will discern how the enzyme activity is regulated, especially through post-translational
modifications of histones and certain histone variants. The enzymatic activity of histones indicates that there
must be a previously undiscovered biological network that shuttles Cu2+ to histones and then distributes the
reaction product (Cu1+) to different parts of the cell for use by proteins in the nucleus, cytoplasm and
mitochondria. In Aim 3, we plan to systematically identify the protein effectors involved in this novel copper
biological network in yeast by utilizing a high-throughput CRISPR-interference (CRISPRi) technology. We aim
to identify the genes and pathways that integrate the enzymatic activity of histones with other cellular functions.
Our proposal will begin to build the scientific foundation for understanding chromatin structure and function as
an enzyme and its impact on eukaryotic biology with instructive consequences for the evolution of the eukaryotic
cell as well as a range of human pathologies such as cancer and neurodegeneration in which copper
homeostasis is altered.

## Key facts

- **NIH application ID:** 10320937
- **Project number:** 5R01GM140106-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Siavash Kurdistani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $452,299
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320937

## Citation

> US National Institutes of Health, RePORTER application 10320937, Understanding the function of histone H3 as an oxidoreductase enzyme (5R01GM140106-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10320937. Licensed CC0.

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