FANCI functions as a repair/apoptosis switch in response to DNA crosslinks.

Cells counter DNA damage through repair or apoptosis, yet a direct mechanism for this choice has remained elusive. When facing interstrand crosslinks (ICLs), the ICL-repair protein FANCI heterodimerizes with FANCD2 to initiate ICL excision. We found that FANCI alternatively interacts with a pro-apoptotic factor, PIDD1, to enable PIDDosome (PIDD1-RAIDD-caspase-2) formation and apoptotic death. FANCI switches from FANCD2/repair to PIDD1/apoptosis signaling in the event of ICL-repair failure. Specifically, removing key endonucleases downstream of FANCI/FANCD2, increasing ICL levels, or allowing damaged cells into mitosis (when repair is suppressed) all suffice for switching. Reciprocally, apoptosis-committed FANCI reverts from PIDD1 to FANCD2 after a failed attempt to assemble the PIDDosome. Monoubiquitination and deubiquitination at FANCI K523 impact interactor selection. These data unveil a repair-or-apoptosis switch in eukaryotes. Beyond ensuring the removal of unrepaired genomes, the switch's bidirectionality reveals that damaged cells can offset apoptotic defects via de novo attempts at lesion repair. [Display omitted] • FANCI binds either pro-repair FANCD2 or pro-apoptotic PIDD1 in response to ICLs • Interactor selection by FANCI is binary and regulated by deubiquitination • Repair failure triggers PIDD1 recruitment, PIDDosome formation, and apoptotic death • Apoptosis failure triggers reversal to FANCD2 and de novo attempts at ICL repair Shah et al. describe a mechanism by which cells decide their fate, repair or self-removal, after DNA damage. The mechanism relies on the ability of a DNA repair effector, FANCI, to engage an apoptotic device in a manner exclusive with its repair activity. [ABSTRACT FROM AUTHOR]