LIVE NATURE WEBCAST
Fanconi anemia pathway mechanism surveys DNA and recognizes double to single-stranded junctions

The Fanconi anemia pathway has become a model system for researchers investigating DNA repair. The Fanconi anemia pathway repairs DNA crosslinks that block DNA replication, and the FANCD2-FANCI (D2-I) protein complex is central to this process as it initiates repair by coordinating DNA incisions around the lesion. However, D2-I is also known to play a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation. It has been unclear how DNA crosslinks are recognized and how D2-I functions in replication fork protection.

This webcast will describe new work using single-molecule imaging that shows that D2-I is a sliding clamp that binds to and diffuses on double-stranded DNA. Strikingly, sliding D2-I stalls upon encountering single-stranded–double-stranded (ss-ds) DNA junctions. Use of cryoEM determined 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 a ssDNA gap, it specifically clamps onto ss-dsDNA junctions. Since ss-dsDNA junctions are found at stalled replication forks, D2-I can identify sites of DNA damage. This data provides a unified molecular mechanism that reconciles the roles of D2-I in recognition and protection of stalled replication forks in multiple DNA repair pathways.

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