biostudies-literatureMason BCancer Research UKBreast Cancer NowAddenbrooke's Charitable Trust, Cambridge University HospitalsWildy Fellowship Department of PathologyBEPE-FAPESPNational Institute for Health Research (NIHR)The Mark Foundation2605-2620https://www.ebi.ac.uk/biostudies/studies/S-EPMC7320043biostudies-literatureUnknown77(13)In cancer, many genes are mutated by genome rearrangement, but our understanding of the functional consequences of this remains rudimentary. Here we report the F-box protein encoded by FBXL17 is disrupted in the region of the gene that encodes its substrate-binding leucine rich repeat (LRR) domain. Truncating Fbxl17 LRRs impaired its association with the other SCF holoenzyme subunits Skp1, Cul1 and Rbx1, and decreased ubiquitination activity. Loss of the LRRs also differentially affected Fbxl17 binding to its targets. Thus, genomic rearrangements in FBXL17 are likely to disrupt SCF^Fbxl17-regulated networks in cancer cells. To investigate the functional effect of these rearrangements, we performed a yeast two-hybrid screen to identify Fbxl17-interacting proteins. Among the 37 binCellular and molecular life sciences : CMLSFbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.PMC7320043C1023/A14545C1023/A91402013NovPhD17214545NF-SI-0611-10154NF-SI-0515-100902012/09241-8Laman HTeixeira FRManzano Garcia RFlach SEdwards PAWAbraham JEMason BCaldas CRueda OMfalseFbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.In cancer, many genes are mutated by genome rearrangement, but our understanding of the functional consequences of this remains rudimentary. Here we report the F-box protein encoded by FBXL17 is disrupted in the region of the gene that encodes its substrate-binding leucine rich repeat (LRR) domain. Truncating Fbxl17 LRRs impaired its association with the other SCF holoenzyme subunits Skp1, Cul1 and Rbx1, and decreased ubiquitination activity. Loss of the LRRs also differentially affected Fbxl17 binding to its targets. Thus, genomic rearrangements in FBXL17 are likely to disrupt SCF^Fbxl17-regulated networks in cancer cells. To investigate the functional effect of these rearrangements, we performed a yeast two-hybrid screen to identify Fbxl17-interacting proteins. Among the 37 bin2020-01-01T00:00:00Z2020 Jul2026-04-30T11:23:10.452Z2020-07-05T07:05:54ZS-EPMC73200433156007710.1007/s00018-019-03306-y