# Molecular Pathogenesis of Fanconi Anemia

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $431,370

## Abstract

PROJECT SUMMARY
Fanconi Anemia (FA) is a rare autosomal recessive genetic disease characterized by congenital defects, bone
marrow failure, cancer predisposition, and cellular hypersensitivity to DNA crosslinking agents (ICLs). FA is
caused by mutations in one of 23 genes whose protein products collaborate in a pathway required for
removing cytotoxic interstrand crosslinks (ICLs) from DNA. The D'Andrea laboratory has identified many of the
molecular players and processes in the FA/BRCA pathway. In collaboration with the Soulier laboratory, we
recently identified REV7 as the FA gene, FANCV. This was a key finding, since REV7/FANCV is emerging as
a critical protein affecting several different DNA repair processes, by engaging with different binding partners
through its C-terminal “seatbelt” domain. When the seatbelt of REV7 is bound to SHLD3, it functions upstream
in NHEJ. When the seatbelt of REV7 is bound to REV3, it functions as a translesion (TLS) polymerase, Polζ,
required for bypassing an unhooked DNA crosslink, generated by the upstream FA proteins. Thus, REV7
deficiency, like the deficiency of other FA proteins, causes sensitivity to Mitomycin C (MMC), an ICL-inducing
agent. Through preliminary studies for this grant, we identified novel REV7 interactors by IP-MS. Interestingly,
we identified the binding partner, TRIP13, a novel ATPase which flips REV7 into an open conformation and
releases REV3 and inactivates the FA/BRCA pathway. We also identified the REV7-binding protein
SHLD2/FAM35A. Knockdown of this protein, like REV7 knockdown, disrupts the FA/BRCA pathway. The
Specific Aims for the next five years of this grant are 1) to determine the role of the ATPase TRIP13 in the
suppression of the FA/BRCA Pathway 2) to determine the role of the REV7/FANCV protein and its binding
partner SHLD2/FAM35A in the activation of the FA/BRCA pathway 3) to employ knockout mouse models for
REV7/FANCV and TRIP13 to evaluate the regulation of the FA/BRCA pathway.

## Key facts

- **NIH application ID:** 10083752
- **Project number:** 5R01HL052725-26
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** ALAN D. D'ANDREA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,370
- **Award type:** 5
- **Project period:** 1994-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083752

## Citation

> US National Institutes of Health, RePORTER application 10083752, Molecular Pathogenesis of Fanconi Anemia (5R01HL052725-26). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10083752. Licensed CC0.

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