# The multifaceted role of the Fanconi anemia tumor suppressor pathway in facilitating DNA replication

> **NIH NIH R00** · RBHS -CANCER INSTITUTE OF NEW JERSEY · 2020 · $325,515

## Abstract

PROJECT SUMMARY
During DNA replication, each cell copies three billion nucleotides/bases within a period of six-eight hours. A
complex and well-coordinated network of proteins, work in tandem to ensure the successful completion of this
process. The inactivation of any one these proteins, can lead to disastrous consequences like genomic
instability, cancer and many other debilitating diseases. Accordingly, the deficiency in any one of nineteen such
proteins results in a devastating disorder called Fanconi anemia (FA). FA is a rare genetic disorder
characterized by bone marrow failure (BMF), hematological abnormalities and a very high incidence of
malignancies. BMF is a leading cause of mortality in FA patients [67] and pancytopenia, thrombocytopenia and
anemia are common in FA patients [68]. In addition, the FA patients have a progressive decline in
hematopoietic stem and progenitors cells (HSPC) [67, 69, 70], which is thought be responsible for the bone
marrow failure in patients. However, the primary mechanisms underlying HSPC decline, BMF and cancer
predisposition in FA patients have remained elusive. Over the last decade, an increasing number of
proteins functioning in important cellular pathways are being classified as FA proteins, highlighting the
complexity of FA. While the DNA repair-mediated functions of FA proteins are widely implicated in the etiology
of the disease, there is a driving need to understand the entire spectrum of cellular functions of FA proteins
outside crosslink repair. Recent reports suggest a new role for the FA pathway in DNA replication. The
long-term goal of this proposal is to investigate defective replication as one of the early driving forces of
genomic instability, leading to hematopoietic stem and progenitor cell attrition, in Fanconi anemia patients. The
genome-wide role of the FA proteins in DNA replication will be better understood by investigating their
involvement facilitating the replication of regions of the genome that are most vulnerable to replication stress,
such as fragile sites. The primary goal of this proposal is to elucidate the mechanistic involvement of the FA
proteins in DNA replication, using fragile sites as model genomic loci. Preliminary studies by Dr. Madireddy,
show that the FA proteins, specifically FANCD2, facilitates the replication of common fragile sites, even in the
absence of exogenous replicative stress. The focus of Aim 1 is to identify structural elements, which potentially
stall replication forks, in the absence of FA proteins and to elucidate the mechanism/s by which FANCD2
alleviates replication pausing at CFS. To understand why DNA replication initiation is altered, in the absence of
the FANCD2 protein, Aim 2 investigates the chromatin remodeling role of FANCD2 is this process. Finally,
using FA iPSC and reprogrammed hematopoietic stem cells (HSC) as model systems, Aim 3 investigates
whether replication defects and the associated genomic instability are contributing to ste...

## Key facts

- **NIH application ID:** 9996781
- **Project number:** 5R00HL136870-05
- **Recipient organization:** RBHS -CANCER INSTITUTE OF NEW JERSEY
- **Principal Investigator:** Advaitha Madireddy
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,515
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996781

## Citation

> US National Institutes of Health, RePORTER application 9996781, The multifaceted role of the Fanconi anemia tumor suppressor pathway in facilitating DNA replication (5R00HL136870-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9996781. Licensed CC0.

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