Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48.
Loading...
Embargo End Date
ICR Authors
Authors
Velimezi, G
Robinson-Garcia, L
Muñoz-Martínez, F
Wiegant, WW
Ferreira da Silva, J
Owusu, M
Moder, M
Wiedner, M
Rosenthal, SB
Fisch, KM
Moffat, J
Menche, J
van Attikum, H
Jackson, SP
Loizou, JI
Robinson-Garcia, L
Muñoz-Martínez, F
Wiegant, WW
Ferreira da Silva, J
Owusu, M
Moder, M
Wiedner, M
Rosenthal, SB
Fisch, KM
Moffat, J
Menche, J
van Attikum, H
Jackson, SP
Loizou, JI
Document Type
Journal Article
Date
2018-06-11
Date Accepted
2018-05-14
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.
Citation
Nature Communications, 2018, 9 (1), pp. 2280 -
Source Title
Nature Communications
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Target Val & Genome Stab