| Autor: |
Shah, R.B., Kernan, J.L., van Hoogstraten, A., Ando, K., Li, Y., Belcher, A.L., Mininger, I., Bussenault, A.M., Raman, R., Ramanagoudr-Bhojappa, R., Huang, T.T., D’Andrea, A.D., Chandrasekharappa, S.C., Aggarwal, A.K., Thompson, R., Sidi, S. |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| ISSN: |
1534-5807 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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