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.