# Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $427,763

## Abstract

PROJECT SUMMARY
The BRCA1 protein functions in homologous recombination (HR), a DNA repair process that uses the
undamaged sister chromatid to carry out high fidelity repair of DNA double strand breaks (DSBs). Genetic
knockout of HR genes in mice demonstrated that Brca1 and the process of HR are critical for viability. In contrast,
loss of the BRCA1 wild-type allele provides a growth advantage and cells are positively selected during cancer
initiation in patients with germline BRCA1 mutations. In our preliminary analyses, we show that the BRCA1
mutant allele is invariably retained in cancers derived from patients with germline mutations. Interestingly, Brca1
mutant alleles have been shown to prolong embryonic viability in Brca1 null backgrounds, suggesting partial
rescue of full-length Brca1 activity. In our recently published studies, we show that BRCA1 mutant alleles are
capable of generating truncated proteins and promote residual HR in BRCA1 mutant cancers. In this proposal,
we will investigate the importance of BRCA1 mutant alleles and HR for cell and tumor viability in BRCA1 mutant
cancers. Furthermore, cells that are deficient in HR DNA repair, such as those lacking functional BRCA1 or
BRCA2, are highly sensitive to platinum and PARP inhibition (PARPi). However, emerging data indicate that
PARPi therapy may benefit only a subset of BRCA1 mutation carriers. In the second part of this proposal, we
will uncover mechanisms that elevate HR to a level required for platinum and PARPi resistance. We show that
proteins generated from BRCA1185delAG and BRCA1C61G alleles fail to interact with BARD1, lack ubiquitin ligase
activity, and are only capable of providing moderate platinum and PARPi resistance. We hypothesize that
BRCA1-BARD1 ubiquitin ligase activity is important for more robust levels of HR that is necessary for therapy
resistance. In preliminary data, we identified RNF7 and RNF207 as novel ubiquitin regulators that demonstrated
increased expression in PARPi resistant BRCA1185delAG and BRCA1C61G clones, and compensate for ubiquitin
ligase deficient-BRCA1 proteins. We will manipulate the expression of ubiquitin ligase proteins and measure
DNA repair, PARPi and cisplatin sensitivity in vitro and in vivo. Proteins that contribute to resistance will be
assessed for expression in PDX models as well as primary tumors. Using these approaches, we will address the
following Specific Aims: 1) investigate the role of BRCA1 mutant alleles in maintaining HR and cancer viability;
and 2) investigate HR-promoting mechanisms contributing to therapy resistance. Our work will ultimately
contribute to the development of biomarkers that predict therapy response and reveal novel targets for chemo-
sensitization.

## Key facts

- **NIH application ID:** 9996515
- **Project number:** 5R01CA214799-04
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Neil Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,763
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996515

## Citation

> US National Institutes of Health, RePORTER application 9996515, Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers (5R01CA214799-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996515. Licensed CC0.

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