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

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. However, D2-I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation.

The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination.

DNA interstrand cross-links are tumor-inducing lesions that block DNA replication and transcription. When cross-links are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2-FANCI clamp by the Fanconi anemia core complex. Monoubiquitinated FANCD2-FANCI is locked onto DNA and recruits nucleases that mediate DNA repair.