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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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BRCA1 Protein / metabolism
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CRISPR-Cas Systems
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Cell Line
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Chromosomal Instability
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DNA Damage
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DNA Repair / genetics*
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DNA Repair / physiology*
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Fanconi Anemia / genetics*
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Fanconi Anemia / metabolism*
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Fanconi Anemia / therapy
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Fanconi Anemia Complementation Group A Protein / deficiency
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Fanconi Anemia Complementation Group A Protein / genetics
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Fanconi Anemia Complementation Group A Protein / metabolism
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Fanconi Anemia Complementation Group C Protein / deficiency
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Fanconi Anemia Complementation Group C Protein / genetics
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Fanconi Anemia Complementation Group C Protein / metabolism
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Fanconi Anemia Complementation Group D2 Protein / deficiency
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Fanconi Anemia Complementation Group D2 Protein / genetics
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Fanconi Anemia Complementation Group D2 Protein / metabolism
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Fanconi Anemia Complementation Group G Protein / deficiency
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Fanconi Anemia Complementation Group G Protein / genetics
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Fanconi Anemia Complementation Group G Protein / metabolism
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Fanconi Anemia Complementation Group Proteins / deficiency
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Fanconi Anemia Complementation Group Proteins / genetics
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Fanconi Anemia Complementation Group Proteins / metabolism
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Gene Knockout Techniques
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Genetic Therapy
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Histones / metabolism
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Humans
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Mutation
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Rad51 Recombinase / metabolism
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Ubiquitin-Specific Proteases / deficiency
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Ubiquitin-Specific Proteases / genetics*
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Ubiquitin-Specific Proteases / metabolism*
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Ubiquitination
Substances
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BRCA1 Protein
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BRCA1 protein, human
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FANCA protein, human
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FANCC protein, human
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FANCD2 protein, human
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FANCG protein, human
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FANCI protein, human
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Fanconi Anemia Complementation Group A Protein
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Fanconi Anemia Complementation Group C Protein
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Fanconi Anemia Complementation Group D2 Protein
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Fanconi Anemia Complementation Group G Protein
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Fanconi Anemia Complementation Group Proteins
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Histones
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RAD51 protein, human
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Rad51 Recombinase
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USP48 protein, human
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Ubiquitin-Specific Proteases