Bythell-Douglas, R. and van Twest, S. and Abbouche, L. and Dunn, E. and Coulthard, R.J. and Briggs, D.C. and Murphy, V. and Zhang, X. and Tan, W. and Henrikus, S.S. and Qian, D. and Wu, Y. and Wolf, J. and Rigoreau, L. and Shakeel, S. and Chapman, K.L. and McDonald, Neil Q. and Deans, A.J. (2025) Structural basis of Fanconi anemia pathway activation by FANCM. The EMBO Journal , ISSN 0261-4189.
![[img]](https://eprints.bbk.ac.uk/style/images/fileicons/text.png) |
Text
55814.pdf - Published Version of Record Available under License Creative Commons Attribution. Download (13MB) |
Abstract
FANCM is crucial in genome maintenance, functioning in the Fanconi anemia (FA) pathway, alternative lengthening of telomeres (ALT), and replication fork protection. FANCM recognizes branched DNA structures and promotes their remodeling through ATP-dependent branch migration. The protein has emerged as a promising therapeutic target due to synthetic lethal interactions with BRCA1, SMARCAL1, and RAD52, and in ALT-positive cancers. Here we present crystal structures of FANCM’s N-terminal ATP-dependent translocase domain (2.2 Å) and C-terminal FAAP24-bound region (2.4 Å), both complexed with branched DNA. Through structural analysis, biochemical reconstitution, and cellular studies, we demonstrate that FANCM employs two distinct mechanisms: an ATP-dependent branch migration activity essential for DNA damage survival, and a branched DNA-binding mode that enhances FANCD2-FANCI monoubiquitination through FA core complex interaction. The N-terminal translocase domain specifically recognizes DNA junctions through multiple key elements, while the C-terminal FAAP24-binding domain engages adjacent double-stranded DNA. Our results reveal how FANCM evolved from an ancient DNA repair motor into a sophisticated sensor that couples DNA damage recognition to selective pathway activation, providing a structural framework for developing targeted therapeutics.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 24 Jun 2025 10:44 |
| Last Modified: | 18 Sep 2025 10:54 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/55814 |
Statistics
Additional statistics are available via IRStats2.
Archive Staff Only (login required)
