PUBLICATION
FANCI functions as a repair/apoptosis switch in response to DNA crosslinks
- Authors
- 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.
- ID
- ZDB-PUB-211109-26
- Date
- 2021
- Source
- Developmental Cell 56: 2207-2222.e7 (Journal)
- Registered Authors
- Chandrasekharappa, Settara, Kernan, Jennifer, Sidi, Samuel, Thompson, Ruth
- Keywords
- DNA interstrand crosslink, DNA repair, FANCD2, FANCI, PIDD1, PIDDosome, apoptosis, molecular switch, monoubiquitination, repair failure
- MeSH Terms
-
- Animals
- Apoptosis/physiology*
- CRADD Signaling Adaptor Protein/metabolism
- Cell Line, Tumor
- Chromatin/metabolism
- DNA/metabolism
- DNA Damage/physiology
- DNA Repair/physiology*
- Death Domain Receptor Signaling Adaptor Proteins/metabolism
- Fanconi Anemia/metabolism
- Fanconi Anemia Complementation Group D2 Protein/metabolism
- Fanconi Anemia Complementation Group D2 Protein/physiology
- Fanconi Anemia Complementation Group Proteins/metabolism*
- Fanconi Anemia Complementation Group Proteins/physiology
- HeLa Cells
- Humans
- Ubiquitination
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism
- PubMed
- 34256011 Full text @ Dev. Cell
Citation
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. (2021) FANCI functions as a repair/apoptosis switch in response to DNA crosslinks. Developmental Cell. 56:2207-2222.e7.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping