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

Pablo Alcón, Artur P. Kaczmarczyk, Korak Kumar Ray, Themistoklis Liolios, Guillaume Guilbaud, Tamara Sijacki, Yichao Shen, Stephen H. McLaughlin, Julian E. Sale, Puck Knipscheer, David S. Rueda () and Lori A. Passmore ()
Additional contact information
Pablo Alcón: MRC Laboratory of Molecular Biology
Artur P. Kaczmarczyk: Imperial College London
Korak Kumar Ray: Imperial College London
Themistoklis Liolios: Hubrecht Institute–KNAW and University Medical Center Utrecht
Guillaume Guilbaud: MRC Laboratory of Molecular Biology
Tamara Sijacki: MRC Laboratory of Molecular Biology
Yichao Shen: MRC Laboratory of Molecular Biology
Stephen H. McLaughlin: MRC Laboratory of Molecular Biology
Julian E. Sale: MRC Laboratory of Molecular Biology
Puck Knipscheer: Hubrecht Institute–KNAW and University Medical Center Utrecht
David S. Rueda: Imperial College London
Lori A. Passmore: MRC Laboratory of Molecular Biology

Nature, 2024, vol. 632, issue 8027, 1165-1173

Abstract: Abstract 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 lesion1. However, D2–I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation2–4. 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 lesions5. 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07770-w Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:632:y:2024:i:8027:d:10.1038_s41586-024-07770-w

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07770-w

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().