FANCI functions as a repair/apoptosis switch in response to DNA crosslinks.
Dev Cell
; 56(15): 2207-2222.e7, 2021 08 09.
Article
en En
| MEDLINE
| ID: mdl-34256011
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Apoptosis
/
Reparación del ADN
/
Proteínas del Grupo de Complementación de la Anemia de Fanconi
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Dev Cell
Asunto de la revista:
EMBRIOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Níger
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
/
UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA