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Nat Commun. 2018 Jun 11;9(1):2280. doi: 10.1038/s41467-018-04649-z.

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

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria.
2
The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
3
Department of Human Genetics, Leiden University Medical Center, Leiden, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
4
Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, 9500 Gilman Drive #0681, La Jolla, CA, 92093, USA.
5
Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 1A8, Canada.
6
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. jloizou@cemm.oeaw.ac.at.

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.

PMID:
29891926
PMCID:
PMC5996029
DOI:
10.1038/s41467-018-04649-z
[Indexed for MEDLINE]
Free PMC Article

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