# The role of microhomology-mediated end joining in Fanconi anemia pathogenesis

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2021 · $467,500

## Abstract

PROJECT SUMMARY
Children with Fanconi anemia (FA) demonstrate developmental disorders that include short stature,
musculoskeletal defects, cancer predisposition, bone marrow failure (BMF) and anemia. In a significant
proportion of cases, FA is associated with biallelic mutations in the hereditary breast and ovarian cancer (HBOC)
genes. Pre-clinical FA studies have largely relied on transgenic animal models. However, currently available FA
mouse models are born without developmental defects and hematological abnormalities have to be chemically
induced. Our laboratory has developed a new Brca1CC mutant mouse model with a 3-amino acid deletion in the
coiled-coil (CC) domain of Brca1 that specifically disrupts the Brca1-Palb2 association, resulting in loss of Rad51
loading and HR deficiency. Notably, Brca1CC homozygous mice are born at sub-Mendelian ratios, and neo-natal
mice demonstrate a range of phenotypes analogous to FA in humans, including short stature, BMF with severe
anemia, and adult mice develop leukemia. Therefore, Brca1CC mice closely resemble human FA and provide a
new tool to gain unprecedented insight into biological pathways that underpin FA etiology. Both homologous
recombination (HR) and microhomology-mediated end joining (MMEJ) are double stranded DNA break (DSB)
repair pathways that are initiated by DNA end resection, a process where DSBs are resected by nucleases to
form single stranded (ss)DNA regions. In preliminary data, we examined human FA patient cells, as well as
Brca1CC MEFs, for HR and MMEJ activity. Interestingly, while HR was lowered, MMEJ was hyperactivated in FA
cell lines. We now hypothesize that hyperactive DNA end resection and MMEJ promote the molecular
pathogenesis of FA. We will address the following Specific Aims: 1) identify DNA repair pathways that are
hyperactive in FA; 2) uncover mechanisms that promote FA embryonic development and pathogenesis; and 3)
examine the effects of MMEJ inhibition on FA pathogenesis. Collectively, the proposed experiments will yield
new insight into DNA repair mechanisms that promote genome instability and FA.

## Key facts

- **NIH application ID:** 10086502
- **Project number:** 5R01HL150190-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Neil Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,500
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086502

## Citation

> US National Institutes of Health, RePORTER application 10086502, The role of microhomology-mediated end joining in Fanconi anemia pathogenesis (5R01HL150190-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086502. Licensed CC0.

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