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, Lori A Passmore

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

2 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1165-1173
Aantal pagina's9
TijdschriftNature
Volume632
Nummer van het tijdschrift8027
DOI's
StatusGepubliceerd - aug. 2024

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