RT Journal Article SR Electronic T1 Intergenic splicing between four adjacent UGT genes (2B15, 2B29P2, 2B17, 2B29P1) gives rise to variant UGT proteins that inhibit glucuronidation via protein-protein interactions JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.118.111773 DO 10.1124/mol.118.111773 A1 Dong Gui Hu A1 Julie-Ann Hulin A1 Dhilushi D Wijayakumara A1 Ross A McKinnon A1 Peter I Mackenzie A1 Robyn Meech YR 2018 UL http://molpharm.aspetjournals.org/content/early/2018/06/29/mol.118.111773.abstract AB Recent studies have investigated alternative splicing profiles of UGT genes and identified over 130 different alternatively spliced UGT transcripts. Although UGT genes are highly clustered, the formation of chimeric transcripts by intergenic splicing between two or more UGT genes has not yet been reported. This study identified twelve chimeric transcripts (chimeras A-L) containing exons from two or three genes of the four neighbouring UGT genes (UGT2B15, UGT2B29P2, UGT2B17, and UGT2B29P1) in human liver and prostate cancer cells. These chimeras typically contain the first five exons of UGT2B15 or UGT2B17 (exons 1-5) spliced to a terminal exon (exon 6) from a downstream UGT gene. Hence they encode truncated UGTs with novel C-terminal peptides. Functional assays of representative chimeric UGT proteins (termed chimeric UGT2B15 and chimeric UGT2B17) showed that they are inactive and can repress the activity of wild-type UGTs. Co-immunoprecipitation assays demonstrated heterotypic interactions between chimeric UGT2B15 (or chimeric UGT2B17) and the UGT2B7 protein. Thus oligomerization of the chimeric UGTs with wild-type UGTs may explain their inhibitory activity. Studies in breast and prostate cancer cells showed that both wildtype and chimeric UGT2B15 and UGT2B17 transcripts are similarly regulated at the transcriptional level by sex hormones through their canonical promoters but are differentially regulated at the post-transcriptional level by miR-376c via their unique 3'-untranslated regions. In conclusion, the formation of chimeric transcripts by intergenic splicing among UGT genes represents a novel mechanism contributing to the diversity of the human UGT transcriptome and proteome. The differential post-transcriptional regulation of wildtype and variant transcripts by miRNAs may contribute to their deregulated expression in cancer.