# Effects of hydrazone-based G-quadruplex ligands on FANCJ/BRIP1-depleted cancer cells and a Caenorhabditis elegans dog-1−/− strain

## TL;DR

This study shows that a specific G4 ligand, FIM-15, harms cancer cells and worms lacking the FANCJ/DOG-1 protein, suggesting a new cancer treatment strategy.

## Contribution

The study demonstrates synthetic lethality using FIM-15 in FANCJ/DOG-1-deficient cells and organisms.

## Key findings

- FANCJ-knocked-out HeLa cells showed increased sensitivity to FIM-15, causing DNA damage.
- FIM-15 stabilized G4 structures in dog-1−/− nematodes, impairing embryonic development.
- The results support using G4 ligands in therapies targeting FANCJ-defective cancers.

## Abstract

G-quadruplex (G4) DNAs are alternative nucleic acid structures, proposed to play important roles in regulating DNA replication, gene transcription, and translation. Several specialized DNA helicases are involved in cellular G4 metabolism, in some cases with redundant functions. Among them, human FANCJ/BRIP1, which has orthologs in all metazoans, is one of the most powerful G4 resolvases, believed to act mainly at DNA replication forks. Here, we tested the effects of a set of hydrazone-derivative G4 ligands in a FANCJ-knocked-out HeLa cell line and in a Caenorhabditis elegans strain, where DOG-1, a FANCJ ortholog, was disrupted, as a whole organism model system. Our results revealed that loss of FANCJ specifically sensitized cancer cells to FIM-15, a mono-guanylhydrazone derivative bearing the diimidazopyrimidine core, among the tested hydrazone-based compounds and induced enhanced DNA damage in different chromosomal sites including telomeric ends. Moreover, dietary administration of FIM-15 to dog-1−/− nematodes stabilized G4 structures in gonadal cell nuclei and resulted in compromised embryonic development in the first-generation post-treatment. Collectively, our findings unveil a specific vulnerability of FANCJ-knocked-out cancer cells (and DOG-1-lacking worms) to G4 stabilization by the FIM-15 compound. This study provides an important proof-of-principle for use of G4 ligands in synthetic lethality-based therapeutic approaches targeting FANCJ-defective cancer cells.

Graphical Abstract