The BRCA1 isoform, BRCA1-IRIS, operates independently of the full-length BRCA1 in the Fanconi anemia pathway

The tumor suppressor BRCA1 encodes multiple protein products including the canonical BRCA1-p220 (p220), which plays important roles in repair of diverse types of DNA damage. However, contributions of other BRCA1-encoded protein isoforms to DNA damage repair are less clear. Here, we report that the BRCA1-IRIS (IRIS) isoform has critical functions in the Fanconi anemia (FA) pathway and in repair of DNA interstrand crosslinks (ICLs). Loss of IRIS expression sensitizes cells to ICLs and impairs ICL repair. ICL formation stimulates association of IRIS with both FANCD2 and the FA core complex, which promotes FANCD2 recruitment to damage sites. The unique, BRCA1 intron 11-encoded C-terminal tail of IRIS is required for complex formation with FANCD2 and for ICL-inducible FANCD2 mono-ubiquitylation. Collectively, our findings reveal that IRIS plays an essential role, upstream of the p220-directed HR, in the FA pathway through a previously unrecognized mechanism that depends on the IRIS-FANCA-FANCD2 interaction. HighlightsO_LIBRCA1 splicing isoform BRCA1-IRIS is required for interstrand crosslink (ICL) repair. C_LIO_LIBRCA1-IRIS interacts with FANCD2 and promotes its recruitment to sites of ICL damage. C_LIO_LIBRCA1-IRIS, but not BRCA1-p220, promotes ICL-inducible FANCD2 mono-ubiquitylation. C_LIO_LIThe unique C-terminal tail of BRCA1-IRIS is essential for its function in ICL repair. C_LI