Journal Article

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

Loizou, Joanna I., Moffat, Jason, Menche, Jörg, Velimezi, Georgia, Owusu, Michel, Ferreira da Silva, Joana, Robinson-Garcia, Lydia, Jackson, Stephen P., Wiedner, Marc, Wiegant, Wouter W., van Attikum, Haico, Muñoz-Martínez, Francisco, Rosenthal, Sara Brin, Moder, Martin, Fisch, Kathleen M.

2018

Overview

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. Fanconi anemia is a rare disease caused by defective DNA interstrand crosslink repair. Here the authors observe that USP48 deficiencies reduce chromosomal instability in FA-defective cells, suggesting it might be a potential therapeutic target.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/109 / 13/89 / 38/23 / 38/47 / 631/337/1427 / 631/553/2490 / 631/80/86 / Abnormalities / Anemia / Bone cancer / Bone marrow / BRCA1 protein / BRCA1 Protein - metabolism / Cancer / Cell Line / Chromosomal Instability / CRISPR-Cas Systems / Crosslinking / Deactivation / Deoxyribonucleic acid / DNA / DNA Damage / DNA repair / DNA Repair - genetics / DNA Repair - physiology / FANCC protein / Fanconi Anemia - genetics / Fanconi Anemia - metabolism / Fanconi Anemia - therapy / Fanconi Anemia Complementation Group A Protein - deficiency / Fanconi Anemia Complementation Group A Protein - genetics / Fanconi Anemia Complementation Group A Protein - metabolism / Fanconi Anemia Complementation Group C Protein - deficiency / Fanconi Anemia Complementation Group C Protein - genetics / Fanconi Anemia Complementation Group C Protein - metabolism / Fanconi Anemia Complementation Group D2 Protein - deficiency / Fanconi Anemia Complementation Group D2 Protein - genetics / Fanconi Anemia Complementation Group D2 Protein - metabolism / Fanconi Anemia Complementation Group G Protein - deficiency / Fanconi Anemia Complementation Group G Protein - genetics / Fanconi Anemia Complementation Group G Protein - metabolism / Fanconi Anemia Complementation Group Proteins - deficiency / Fanconi Anemia Complementation Group Proteins - genetics / Fanconi Anemia Complementation Group Proteins - metabolism / Fanconi syndrome / Gene Knockout Techniques / Genetic Therapy / Genomes / Genomic instability / Genotoxicity / Health risks / Histones - metabolism / Humanities and Social Sciences / Humans / Inactivation / multidisciplinary / Mutation / Phenotypes / Rad51 Recombinase - metabolism / Rare diseases / Repair / Science / Science (multidisciplinary) / Screens / Stability / Ubiquitin-Specific Proteases - deficiency / Ubiquitin-Specific Proteases - genetics / Ubiquitin-Specific Proteases - metabolism / Ubiquitination