# Examining the Role of RNF168 Activity in BRCA1 Mutant Cancers > **NIH NIH K22** · WASHINGTON UNIVERSITY · 2024 · $154,531 ## Abstract PROJECT SUMMARY/ABSTRACT My career goal is to develop an independent research program focused on DNA damage signaling and how it can be exploited for the treatment of cancer. The work that I propose here explores DNA damage signaling mechanisms in BRCA1 mutant cancers and the implications for PARP inhibitor response. Pathogenic BRCA1 mutations increase the risk of cancer development and impair the homologous recombination (HR) DNA damage response pathway. This HR defect confers vulnerability to DNA damaging agents, including PARP inhibitors. PARP inhibitor efficacy is limited by the development of resistance, often caused by the restoration of HR. In BRCA1 mutant cancers, PARP inhibitor resistance and HR activity can be promoted by expression of mutant BRCA1 proteins. Several types of truncated hypomorphic BRCA1 proteins have been detected, though the mechanism of localization to DNA damage and HR activity has not been established. Recently, we determined that wild-type BRCA1 recruitment to DNA damage can proceed through RNF168-dependent and -independent pathways involving the BRCA1 RING and BRCT domains. In preliminary data, we found that RNF168 depletion impairs tumor growth for some, but not all, BRCA1 mutant cancers. Additionally, we show that some cancer cells are entirely reliant on the RNF168 pathway for HR, whereas others rely on the reciprocal pathway. These findings are in line with transgenic mouse studies where different Brca1 mutant alleles produced contrasting phenotypes upon RNF168 knockout. Here, we explore the possibility that BRCA1 mutation-specific differences arise from the capacity to recruit various hypomorphic BRCA1 proteins to DNA damage. We will use cell line, patient- derived xenograft, and transgenic mouse model systems to address the fundamental question of how the RNF168 pathway contributes to tumor progression, DNA repair, and PARP inhibitor response in different BRCA1 mutant backgrounds. Specifically, we hypothesize that depletion of RNF168 in cancers expressing BRCA1 RING domain-containing hypomorphic proteins will impair tumor progression, eliminate HR activity, and restore sensitivity to PARP inhibitors. To test this hypothesis, we developed PARP inhibitor sensitive and resistant cell line and patient-derived xenograft models that express hypomorphic BRCA1 proteins. Additionally, we generated isogenic expression systems as well as transgenic mice with Rnf168 and various Brca1 mutations. Using these models, we will examine the effects of genetic depletion of RNF168 on tumorigenesis and growth, localization of BRCA1 hypomorphs and other DNA repair proteins, and response to PARP inhibition. These studies will provide mechanistic insight into the repair processes occurring in cancers and assess the potential efficacy of RNF168 pathway-targeted therapeutics. Moreover, funding of this proposal will help me to secure an independent investigator position and lay the foundation for future R01 applications to build a susta... ## Key facts - **NIH application ID:** 10910988 - **Project number:** 5K22CA276631-02 - **Recipient organization:** WASHINGTON UNIVERSITY - **Principal Investigator:** John Krais - **Activity code:** K22 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $154,531 - **Award type:** 5 - **Project period:** 2023-09-01 → 2025-08-05 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10910988 ## Citation > US National Institutes of Health, RePORTER application 10910988, Examining the Role of RNF168 Activity in BRCA1 Mutant Cancers (5K22CA276631-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10910988. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*