FANCD2-FANCI surveys DNA and recognizes double- to single-stranded junctions.

Autor: Alcón P; MRC Laboratory of Molecular Biology, Cambridge, UK., Kaczmarczyk AP; Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK., Ray KK; Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK.; MRC Laboratory of Medical Sciences, London, UK., Liolios T; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands., Guilbaud G; MRC Laboratory of Molecular Biology, Cambridge, UK., Sijacki T; MRC Laboratory of Molecular Biology, Cambridge, UK., Shen Y; MRC Laboratory of Molecular Biology, Cambridge, UK., McLaughlin SH; MRC Laboratory of Molecular Biology, Cambridge, UK., Sale JE; MRC Laboratory of Molecular Biology, Cambridge, UK., Knipscheer P; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands., Rueda DS; Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK. david.rueda@imperial.ac.uk.; MRC Laboratory of Medical Sciences, London, UK. david.rueda@imperial.ac.uk., Passmore LA; MRC Laboratory of Molecular Biology, Cambridge, UK. passmore@mrc-lmb.cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Aug; Vol. 632 (8027), pp. 1165-1173. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1038/s41586-024-07770-w
Abstrakt: DNA crosslinks block DNA replication and are repaired by the Fanconi anaemia pathway. The FANCD2-FANCI (D2-I) protein complex is central to this process as it initiates repair by coordinating DNA incisions around the lesion 1 . However, D2-I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation 2-4 . At present, it is unclear how DNA crosslinks are recognized and how D2-I functions in replication fork protection. Here, using single-molecule imaging, we show that D2-I is a sliding clamp that binds to and diffuses on double-stranded DNA. Notably, sliding D2-I stalls on encountering single-stranded-double-stranded (ss-ds) DNA junctions, structures that are generated when replication forks stall at DNA lesions 5 . Using cryogenic electron microscopy, we determined structures of D2-I on DNA that show that stalled D2-I makes specific interactions with the ss-dsDNA junction that are distinct from those made by sliding D2-I. Thus, D2-I surveys dsDNA and, when it reaches an ssDNA gap, it specifically clamps onto ss-dsDNA junctions. Because ss-dsDNA junctions are found at stalled replication forks, D2-I can identify sites of DNA damage. Therefore, our data provide a unified molecular mechanism that reconciles the roles of D2-I in the recognition and protection of stalled replication forks in several DNA repair pathways.
(© 2024. The Author(s).)
Databáze: MEDLINE
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