Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48
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Authors
Jackson, SP
Velimezi, Georgia
Robinson-Garcia, Lydia
Muñoz-Martínez, Francisco
Wiegant, Wouter
Ferreira da Silva, Joana
Owusu, Michel
Moder, Martin
Wiedner, Marc
Rosenthal, Sara
Fisch, Kathleen
Moffat, Jason
Menche, Jörg
Van Attikum, Haico
Loizou, Joanna
Publication Date
2018-06-11Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Springer Nature
Volume
9
Number
2280 (2018)
Language
eng
Type
Article
This Version
VoR
Metadata
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Jackson, S., Velimezi, G., Robinson-Garcia, L., Muñoz-Martínez, F., Wiegant, W., Ferreira da Silva, J., Owusu, M., et al. (2018). Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48. Nature Communications, 9 (2280 (2018)) https://doi.org/10.1038/s41467-018-04649-z
Abstract
Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). By performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2), we identified the deubiquitylating enzyme USP48 as synthetic viable for FA gene deficiencies. Thus, as compared to
FA-defective cells alone, FA-deficient cells additionally lacking USP48 are less
sensitive to genotoxic stress induced by ICL agents and display enhanced, BRCA1-dependent, clearance of DNA damage. Consequently, USP48 inactivation reduces chromosomal instability of FA-defective cells. Our results highlight a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for FA.
Keywords
cell signalling, DNA damage and repair, genetic interaction
Sponsorship
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-04649-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280696
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