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P01CA275717

Project Grant

Overview

Grant Description
Regulation of BRCA-dependent genome repair via the 53BP1 axis - Abstract

DNA double-strand breaks (DSBs) occur upon exposure of cells to ionizing radiation and chemicals in the environment, and when DNA replication forks become impeded by lesions and obstacles then subsequently collapse.

Two mechanistically distinct DSB repair pathways, namely, homology-directed repair (HDR) and non-homologous DNA end-joining (NHEJ), are responsible for the removal of the majority of DSBs.

Whereas HDR is mostly accurate, NHEJ, while efficient, often entails loss of DNA sequence during repair, and can also generate chromosome translocations and replication fork fusions.

Failure of NHEJ or HDR leads to heightened engagement of alternate end-joining (ALTEJ) and single-strand annealing (SSA), highly mutagenic and otherwise minor pathways, as repair tools.

As such, the choice of DSB repair pathway has a major impact on the maintenance of genome stability, preventing neoplastic transformation of cells, and oncogenesis.

Our program project brings together seven leading NIH-funded laboratories within a highly collaborative and synergistic realm to delineate the mechanisms of HDR and replication fork maintenance, and how HDR is negatively regulated to favor the use of NHEJ as DSB repair tool.

We have assembled three shared resource cores to provide state-of-the-art services in the production of high quality protein preparations for mechanistic experiments, biophysical and structural analyses of protein-ligand interactions and precise measurement of binding constants, and also cellular analyses of DSB repair and replication fork maintenance.

Altogether, we are exceptionally well poised to leverage our deep knowledge of DSB repair mechanisms and leadership to understand how the tumor suppressors BRCA1-BARD1 and BRCA2 function to promote HDR and to overcome the HDR restrictive action of the epigenetic mark reader 53BP1 and its associated factors such as DYNLL1 and the hetero-trimeric CTC1-STN1-TEN1 complex.

As such, our program project will not only exert a major impact in elucidating mechanisms of DSB repair pathway choice and cancer drug resistance, but will also identify novel targets and pathways pivot points to guide the development of new therapeutic strategies to treat incalcitrant breast, ovarian and other cancers.
Funding Goals
TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.
Place of Performance
San Antonio, Texas 782293901 United States
Geographic Scope
Single Zip Code
Analysis Notes
Amendment Since initial award the total obligations have increased 98% from $2,556,071 to $5,073,794.
The University Of Texas Health Science Center At San Antonio was awarded BRCA-Dependent Genome Repair Regulation for Cancer Therapy Project Grant P01CA275717 worth $5,073,794 from National Cancer Institute in September 2024 with work to be completed primarily in San Antonio Texas United States. The grant has a duration of 5 years and was awarded through assistance program 93.393 Cancer Cause and Prevention Research. The Project Grant was awarded through grant opportunity National Cancer Institute Program Project Applications for the Years 2023, 2024, and 2025 (P01 Clinical Trial Optional).

Status
(Ongoing)

Last Modified 8/20/25

Period of Performance
9/1/24
Start Date
8/31/29
End Date
19.0% Complete

Funding Split
$5.1M
Federal Obligation
$0.0
Non-Federal Obligation
$5.1M
Total Obligated
100.0% Federal Funding
0.0% Non-Federal Funding

Activity Timeline

Interactive chart of timeline of amendments to P01CA275717

Transaction History

Modifications to P01CA275717

Additional Detail

Award ID FAIN
P01CA275717
SAI Number
P01CA275717-1230366012
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
C3KXNLTAAY98
Awardee CAGE
0NJ12
Performance District
TX-20
Senators
John Cornyn
Ted Cruz
Modified: 8/20/25