Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48

Georgia Velimezi, Lydia Robinson-Garcia, Francisco Muñoz-Martínez, Wouter W. Wiegant, Joana Ferreira da Silva, Michel Owusu, Martin Moder, Marc Wiedner, Sara Brin Rosenthal, Kathleen M. Fisch, Jason Moffat, Jörg Menche, Haico van Attikum, Stephen P. Jackson and Joanna I. Loizou ()
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Georgia Velimezi: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Lydia Robinson-Garcia: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Francisco Muñoz-Martínez: University of Cambridge
Wouter W. Wiegant: Leiden University Medical Center, Leiden
Joana Ferreira da Silva: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Michel Owusu: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Martin Moder: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Marc Wiedner: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Sara Brin Rosenthal: University of California, San Diego
Kathleen M. Fisch: University of California, San Diego
Jason Moffat: University of Toronto
Jörg Menche: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Haico van Attikum: Leiden University Medical Center, Leiden
Stephen P. Jackson: University of Cambridge
Joanna I. Loizou: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2). 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.

Date: 2018
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DOI: 10.1038/s41467-018-04649-z

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