# Defining the role of BARD1 in nucleosomal ubiquitylation

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $527,185

## Abstract

PROJECT SUMMARY
BARD1 (BRCA1-Associated RING Domain protein-1) is an essential partner of the breast and
ovarian cancer tumor-suppressor protein, BRCA1, and is included in a panel of genes used to
evaluate patients with suspected hereditary cancer predisposition, especially breast and ovarian
cancers. Despite this, little is known about the cellular role of BARD1. This project aims to
address this serious gap in knowledge by defining at a molecular level how BARD1 contributes
to DNA damage repair and to transcriptional repression. An ultimate goal is to enable
predictions regarding potential loss-of-function phenotypes for mutations identified in patients.
BRCA1 and its obligate partner BARD1 form a heterodimeric complex that is implicated in
numerous cellular processes, most notably, transcriptional regulation and DNA repair via
homologous recombination. The sole enzymatic activity directly associated with the
BRCA1/BARD1 complex is as an E3 Ubiquitin ligase. The RING domains of BRCA1 and
BARD1 specifically and uniquely target positions on the tail of nucleosomal histone H2A. The
ability of BRCA1/BARD1 to place these Ub marks is essential to both its transcriptional
repression of certain genes and its function in DNA damage repair by homologous
recombination. While the RING of BRCA1 is required for all ligase activity, breast cancer patient
mutations in the RING of BARD1 display loss-of-function specifically for ubiquitylation of H2A. A
newly determined cryo-EM structure of the BRCA1/BARD1 RING domains sitting atop a
nucleosome reveals that BARD1 dictates the orientation of the E3 ligase and, therefore,
determines the site(s) of modification on H2A. In this project, we will build on this exciting new
structural insight to address how regions outside BARD1’s RING contribute to its function as an
essential partner of BRCA1.

## Key facts

- **NIH application ID:** 10368107
- **Project number:** 5R01CA260834-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** PETER S BRZOVIC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $527,185
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368107

## Citation

> US National Institutes of Health, RePORTER application 10368107, Defining the role of BARD1 in nucleosomal ubiquitylation (5R01CA260834-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10368107. Licensed CC0.

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