# Mechanistic Dissection of the Falconi Anemia Pathway of DNA Damage Response and Repair

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $377,018

## Abstract

Project Summary
Proteins from the Fanconi anemia (FA) pathway play an integral role in DNA repair by homologous
recombination (HR). FA is a multigenic disorder marked by progressive bone marrow failure and a
strong cancer predisposition. Numerous studies have linked mutations in FA genes to familial breast,
pancreatic, and other cancers, and have also provided ample evidence to implicate silencing of FA
genes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNA
damaging agents, DNA crosslinking chemicals and reactive aldehydes in particular, prone to DNA
replicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem from
defects in DNA damage signaling and repair, and FA protein functional and physical interactions have
indicated an important link to the familial breast cancer proteins BRCA1 and BRCA2. The
involvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscores
the need to understand the mechanistic underpinnings of this genome maintenance pathway.
In this project, we will employ a combination of biochemical and in vivo approaches to test the novel
hypotheses that the FA pathway coordinates the prevention and resolution of genotoxic structures
resulting from aberrant transcription events and HR. Aim 1 will focus on the mechanism whereby the
ID2 complex and UAF1-containing complexes engage nucleic acid containing structures and activate
HR. Aim 2 will explore how the FANCM-BLM axis resolves pathogenic RNA containing and other
nucleic acid intermediates in a way that regulates HR activities. The success of this project is
assured by the complementary expertise of the two participating Yale groups, led by Dr Patrick Sung
and Dr Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yale
community. In addition, the PIs have enlisted two investigators, Dr. Claudia Wiese and Dr. Andres
Aguilera, whose expertise will even more elegantly allow the team to interrogate this novel area of
genomic instability. These attributes help ensure that findings of the highest possible impact will be
obtained. Since the biology of FA intersects with cancer biology in general, our project promises to
shed light on critical processes of genomic surveillance as well as common themes of oncogenesis.
We expect our studies to yield insight into common pathways of cancer and to identify novel targets
for manipulation in cancer therapy.

## Key facts

- **NIH application ID:** 9939471
- **Project number:** 5R01CA168635-09
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Gary M Kupfer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,018
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939471

## Citation

> US National Institutes of Health, RePORTER application 9939471, Mechanistic Dissection of the Falconi Anemia Pathway of DNA Damage Response and Repair (5R01CA168635-09). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9939471. Licensed CC0.

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