# Uncovering differential functions of novel BRCA1 complexes

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $49,532

## Abstract

PROJECT SUMMARY / ABSTRACT
 Determination of the increased sensitivity of BRCA1-deficient cells to poly (ADP-ribose) polymerase
(PARP) inhibitors resulted in development of effective and targeted cancer therapies. Approval of PARP
inhibitors as mono- or combination- therapies for breast and ovarian cancers demonstrate the importance of
identifying specific genes and pathways that mediate pathway alterations in cancer cells. With about 450 proteins
participating in double-stranded damage repair (DDR) pathway, it is expected that some of the synergistic
interactions between DDR genes are yet to be discovered. Systematic approaches with large datasets will
accelerate discovery of such interactions by providing functional insights into formation of testable molecular
models.
 The aim of the proposed research plan is to discover new factors involved in DDR and cancer progression
by complementing a genetic-chemical interaction study with mechanistic and structural characterization in an
orthogonal manner. Specific Aims of this proposal are designed to independently reflect the collaborative
expertise of the Krogan lab in deducing biological insights from collection and analysis of large datasets, while
taking advantage of the resources available in UCSF. The goal of Aim1 is to identify BRCA1 interactors that
are functionally important for tumor suppression using a CRISPR-Cas9 based screen. The differential
effects of knocking out around 92 BRCA1-interacting genes, including novel interactors that were identified in
preliminary proteomics studies, on sensitivity to different kinds of chemotherapy drugs will be evaluated. This
screen will be followed by more targeted drug treatments in order discern proteins that form complexes. The
targeted gene selection approach that will be employed here has the advantage of enriching for proteins that are
likely to have related functions. Similar to genetic interaction screens, proteins that are involved in the same
protein complexes are expected to show sensitivity to same kinds of drugs. Aim2 will establish the role of
neddylation and the implications of the GPS1-BRCA1 complex on homologous recombination. The role
of neddylation in homologous recombination is understudied and results have been contradictory. Preliminary
experiments point to a previously unexplored interaction between GPS1, a COP9-signalosome subunit, and
BRCA1. Quantitative and targeted mass spectrometry-based analysis, along with biochemical assays will be
used to study the role of neddylation and COP9 signalosome on BRCA1 levels in the cell. Aim3 will determine
the cryo-EM structure of prevailing BRCA1-complexes. This aim will be completed in collaboration with the
Agard Lab, using a derivatized affinity grid technology. Determination of the structure of BRCA1-complexes will
provide a mechanistic overview of the interactions, as well as enable targeted drug engineering.
 Successful execution of this project will lead to the discovery of new ther...

## Key facts

- **NIH application ID:** 9895422
- **Project number:** 5F32CA239336-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Beril Tutuncuoglu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $49,532
- **Award type:** 5
- **Project period:** 2019-04-01 → 2020-12-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895422

## Citation

> US National Institutes of Health, RePORTER application 9895422, Uncovering differential functions of novel BRCA1 complexes (5F32CA239336-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895422. Licensed CC0.

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