# Defining role of FANCA in genome instability

> **NIH NIH R56** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $474,789

## Abstract

Abstract
One of the most predominant hallmarks driving cancer development is genome instability. It creates genome-
wide diversity that enables cells to acquire additional capabilities required for cancer development and
progression. Most of the ~400 genes known to be mutated and implicated in cancer development are a direct
result of increased genome instability. Therefore, understanding the molecular mechanisms of genome
instability in cancer cells is imperative for the development of novel treatment strategies. Fanconi Anemia (FA)
is a hereditary disorder caused by mutations in at least 22 genes and clinically characterized by bone marrow
failure and predisposition to cancer. This proposal focuses on FANCA, a gene that is mutated in ~64% of the
entire FA patient population. During the preliminary studies, we found that FANCA promotes error-prone DNA
repair that drives genome instability; its expression is upregulated in many cancer types, and the expression
level is strongly associated with breast cancer progression and inversely correlates with cancer patient
survival. Intriguingly, FANCA recruitment to double strand breaks and DNA damage sites requires active
transcription in a KillerRed live cell analysis. More importantly, knockout of FANCA in a triple negative breast
cancer cell MDA-MB-231 initiates cell cycle arrest and cellular senescence and abolishes breast cancer
formation in mice. Based on these preliminary data, we hypothesize that FANCA promotes genome instability,
regulates cell cycle progression, and serves as a vulnerability for cancer intervention. To delineate the role of
FANCA in genome instability and cancer development, we will use a biochemically defined in vitro system, a
transcription-coupled DSB repair reporter system, a KillerRed live cell imaging system, a xenograft mouse
model, and genome-wide instability analysis to accomplish three aims: Aim 1 is to determine the molecular
mechanism of how FANCA contributes to R-loop repair; Aim 2 is to study the role of FANCA in genome
instability and how FANCA is regulated; Aim 3 is to determine the role of FANCA in cell cycle progression and
tumor growth. Completion of this proposal will define a novel role for FANCA in genome instability. This work
will also elucidate the significance of FANCA as a unique, rationale-driven target for cancer treatment. The
outcome of this proposal will expand treatment strategies for cancer patients with elevated FANCA expression
and genome instability.

## Key facts

- **NIH application ID:** 10266209
- **Project number:** 2R56HL131013-05A1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Yanbin Zhang
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,789
- **Award type:** 2
- **Project period:** 2016-07-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266209

## Citation

> US National Institutes of Health, RePORTER application 10266209, Defining role of FANCA in genome instability (2R56HL131013-05A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10266209. Licensed CC0.

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