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

Richa B. Shah, Jennifer L. Kernan, Anya van Hoogstraten, Kiyohiro Ando, Yuanyuan Li, Alicia L. Belcher, Ivy Mininger, Andrei M. Bussenault, Renuka Raman, Ramanagouda Ramanagoudr-Bhojappa, Tony T. Huang, Alan D. D'Andrea, Settara C. Chandrasekharappa, Aneel K. Aggarwal, Ruth Thompson, Samuel Sidi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2207-2222.e7
JournalDevelopmental Cell
Volume56
Issue number15
DOIs
StatePublished - 9 Aug 2021

Keywords

  • DNA interstrand crosslink
  • DNA repair
  • FANCD2
  • FANCI
  • PIDD1
  • PIDDosome
  • apoptosis
  • molecular switch
  • monoubiquitination
  • repair failure

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