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Mechansim of RING-between-RING ubiquitin signaling in DNA repair

Award Number: R01CA303071
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/16/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Mechansim of RING-between-RING ubiquitin signaling in DNA repair - PROJECT SUMMARY Genomic instability caused by defective repair of DNA double-strand breaks (DSBs) is a major contributor to cancer development. DSBs, among the most lethal forms of DNA damage, can arise from ionizing radiation, a common modality in cancer therapy. The repair of DSBs involves a tightly regulated network of proteins and post-translational modifications that coordinate recruitment and activation of DNA repair factors. Ubiquitin signaling plays a central role in assembling these repair complexes. Among E3 ubiquitin ligases, the RING- between-RING (RBR) family is the most recently identified and remains the least characterized, representing a critical gap in our understanding of DNA damage response (DDR) regulation. This project focuses on the RBR E3 ligase ARIH1, which we have identified as a novel DDR factor essential for DSB repair. Preliminary data show that ARIH1 is rapidly recruited to DNA lesions, facilitates homologous recombination, and is required for cell survival following genotoxic stress. We hypothesize that ARIH1 acts downstream of RNF168 to regulate DSB repair pathway choice by modulating DNA end resection at sites of damaged chromatin. Understanding how ARIH1 coordinates DDR is especially relevant to cancer therapy. Radiation-induced DNA damage is more toxic to cancer cells than normal cells due to underlying repair deficiencies. However, acquired resistance to radiation, often driven by restoration of repair capacity, remains a major clinical challenge. Targeting DDR components, particularly ubiquitin-dependent signaling hubs like ARIH1, offers a promising strategy to overcome such resistance and improve therapeutic response. To achieve our objectives, we will pursue the following specific aims: 1. Determine the molecular regulation of ARIH1 at damaged chromatin: We will define upstream signaling pathways and post-translational modifications (e.g., phosphorylation and ubiquitination) that govern ARIH1 recruitment and activation upon DNA damage. 2. Characterize the biological function of ARIH1 in genome stability maintenance: Using genetic and cell-based assays, we will assess the role of ARIH1 in pathway choice, DNA repair kinetics, and checkpoint activation following genotoxic stress. 3. Elucidate how ARIH1 regulates DNA end resection: We will use tunable dTAG-mediated ARIH1 depletion to dissect its role in promoting end resection and antagonizing resection-suppressive complexes. Additionally, we will explore the therapeutic implications of targeting ARIH1 in the context of radiation and PARP inhibitor resistance. Successful completion of this work will define a novel ubiquitin signaling axis in DSB repair, advancing our understanding of DDR regulation and resistance mechanisms. This may open new avenues for radiosensitization and combination therapies that exploit DNA repair vulnerabilities in cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $482,637 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	1	6/18/2026	NEW	$482,637
														Subtotal = $482,637

Grand Total All Awards = $482,637

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Mechansim of RING-between-RING ubiquitin signaling in DNA repair

Award Number: R01CA303071

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/16/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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