@article{a2337c8bf072448d9c633045931fd87d,
title = "FANCI functions as a repair/apoptosis switch in response to DNA crosslinks",
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.",
keywords = "DNA interstrand crosslink, DNA repair, FANCD2, FANCI, PIDD1, PIDDosome, apoptosis, molecular switch, monoubiquitination, repair failure",
author = "Shah, {Richa B.} and Kernan, {Jennifer L.} and {van Hoogstraten}, Anya and Kiyohiro Ando and Yuanyuan Li and Belcher, {Alicia L.} and Ivy Mininger and Bussenault, {Andrei M.} and Renuka Raman and Ramanagouda Ramanagoudr-Bhojappa and Huang, {Tony T.} and D'Andrea, {Alan D.} and Chandrasekharappa, {Settara C.} and Aggarwal, {Aneel K.} and Ruth Thompson and Samuel Sidi",
note = "Funding Information: We thank R. Baer, R. Cagan, R. Krauss, M. O{\textquoteright}Connell, and S. Sarti for helpful discussions; P. Liu and Y. Gupta for technical assistance; C. Franco and D. Carles for zebrafish care; and A. Smogorzewska, L. Zou, Y. Zhang, A. Sobeck, T. Taniguchi, M. Cohn, and J. Brody for critical reagents. Y.L. was supported by a National Cancer Center postdoctoral fellowship award. R.R.-B. and S.C.C. acknowledge the support from the Intramural Research Program of the National Genome Research Institute of NIH. T.T.H. was supported by grants from NIH/ NIGMS ( GM107257 ) and V Foundation for BRCA Research . A.D.D. was supported by NIH/ NHLBI ( R37HL052725 ). A.K.A. was supported by NIH/ NIGMS ( R35GM131780 ). R.T. was supported by a Royal Society Dorothy Hodgkin fellowship ( DH160106 ) and Royal Society grants RGF/R1/181008 and RGF/EA/180015 . S.S. was supported by grants from NIH/ NCI ( R01CA178162 ), NIH/ NIGMS ( RO1GM135301 ), Searle Scholars Program ( 11-SSP-196 ), Pershing Square Sohn Cancer Research Alliance and New York Community Trust ( P16-000373 ), Claudia Adams Barr Award (PS# 9617093 ), and JJR Foundation (Young Cancer Research Scientist Award). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "9",
doi = "10.1016/j.devcel.2021.06.010",
language = "English",
volume = "56",
pages = "2207--2222.e7",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "15",
}