🧬 New from crystal structures from our lab in EMBO Journal! We reveal how the FANCM enzyme, an emerging therapeutic target it cancer, has evolved to specifically recognise branched DNA and activate the Fanconi anaemia pathway of DNA repair. doi.org/10.1038/s443... 🧵👇 - ThreadSky

genomestability.bsky.social • 17 days ago

🧬 New from crystal structures from our lab in EMBO Journal! We reveal how the FANCM enzyme, an emerging therapeutic target it cancer, has evolved to specifically recognise branched DNA and activate the Fanconi anaemia pathway of DNA repair. https://doi.org/10.1038/s44318-025-00468-3 🧵👇

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trakselis.bsky.social•17 days ago

Congratulations. This looks great!

genomestability.bsky.social•17 days ago

Using our complete biochemical reconstitution system, we show that FANCM stimulates FANCD2/FANCI monoubiquitination by FA core complex in DNA structure-dependent manner. It promotes stable clamp formation even with USP1:UAF1 deubiquitinase present.

genomestability.bsky.social•17 days ago

And here is what FANCM translocase domain bound to 3'flap hairpin DNA looks like!

genomestability.bsky.social•17 days ago

Actually, the protein has evolved from the same ancestor as the dsRNA immune receptor proteins RIG-I and MDA-5, and the siRNA processing enzyme Dicer, and the DNA repair protein XPF.

genomestability.bsky.social•17 days ago

But FANCM arranges itself on DNA very differently. Using a brand new DNA migration assay we show that several key DNA-binding residues contact the DNA junction (green), while others (yellow) grab onto the splayed DNA so that ATP hydrolysis is converted to forward momentum.

genomestability.bsky.social•17 days ago

🧩 We also have a new structure of FANCM-CTD:FAAP24, also co-crystallised with splayed DNA. The two ends of the protein cooperative in recognition of branched DNA substrates at replication forks and other DNA junctions.

genomestability.bsky.social•17 days ago

Structure-specific DNA binding, not ATP hydrolysis, is required for FANCD2:FANCI monoubiquitination.

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