# Molecular Pathogenesis of Fanconi Anemia

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $445,000

## Abstract

Project Summary
 REV7/FANCV is a versatile DNA repair protein. It binds to REV3 in the Fanconi Anemia/BRCA
pathway, and it binds to SHLD3 in the NHEJ repair pathway. REV7 has at least one additional seatbelt-binding
partner, CHAMP1. CHAMP1 is a little-known but highly conserved zinc finger protein, first identified as a REV7
interactor. CHAMP1 localizes to chromosomes, recruits REV7 to spindles, and plays a role in kinetochore-
microtubule interactions. Germline heterozygous mutations in CHAMP1 are associated with a rare syndromic
form of intellectual disability and dysmorphic features in humans, with some cellular and clinical similarities to
Fanconi Anemia, though the relevance of this disease to FA has previously been unexplored. We have very
recently shown that the binding of CHAMP1 to REV7 promotes DSB end resection and HR repair (Li et al,
2022). The CHAMP1 protein binds to the seatbelt domain of REV7, thereby increasing Homologous
Recombination repair and competing with the binding of SHLD3 or REV3 to REV7. CHAMP1 is a component
of a large, multisubunit heterochromatin complex, containing CHAMP1, POGZ, and HP1α (the so-called
CHAMP1 complex). We have shown that patient-derived mutations in the CHAMP1 protein disrupt the
CHAMP1 complex and disrupt HR repair, leading to a characteristic phenotype and drug sensitivity of the
peripheral blood lymphocytes of CHAMP1 patients. Interestingly, we have now shown that the CHAMP1
complex accumulates at telomeres (i.e., critical concentrated sites heterochromatin) and maintains telomere
length via its HR activity. Although most human tumor cells rely on telomerase to maintain telomere length,
many other human tumors use the ALT (Alternative Lengthening of Telomeres) Pathway, an HR-driven
pathway, to maintain telomeres and to avoid replication senescence. Importantly, we have now shown that
ALT tumor cells depend on the HR activity of the CHAMP1 complex, providing a molecular basis of the
CHAMP1 syndrome. Knockdown of the CHAMP1 complex in ALT tumor cells results in accelerated telomere
shortening. Accordingly, the ALT pathway and the CHAMP1 complex are now highly attractive targets for
cancer therapy. The Specific Aims of the current application are to analyze the structure of the CHAMP1
complex and to determine its role in HR repair and Telomere Length Maintenance.
1

## Key facts

- **NIH application ID:** 10795380
- **Project number:** 2R01HL052725-29
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** ALAN D. D'ANDREA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,000
- **Award type:** 2
- **Project period:** 1994-08-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795380

## Citation

> US National Institutes of Health, RePORTER application 10795380, Molecular Pathogenesis of Fanconi Anemia (2R01HL052725-29). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10795380. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*