title: Accurate splicing of HDAC6 pre-mRNA requires SON.
abstract: Pre-mRNA splicing requires proper splice site selection mediated by many factors including snRNPs and serine-arginine rich (SR) splicing factors. Our lab previously reported that the SR-like protein SON maintains organization of pre-mRNA splicing factors in nuclear speckles as well as splicing of many human transcripts including mRNAs coding for the chromatin-modifying enzymes HDAC6, ADA and SETD8. However, the mechanism by which SON maintains accurate splicing is unknown. To build tools for understanding SON-dependent pre-mRNA splicing, we constructed a minigene reporter plasmid driving expression of the genomic sequence spanning exons 26 through 29 of HDAC6. Following SON depletion, we observed altered splicing of HDAC6 reporter transcripts that showed exclusion of exons 27 and 28, reflecting the splicing patterns of endogenous HDAC6 mRNA. Importantly, loss of HDAC6 biological function was also observed, as indicated by truncated HDAC6 protein and corresponding absence of aggresome assembly activities of HDAC6 binding-of-ubiquitin zinc finger (BUZ) domain. We therefore propose that SON-mediated splicing regulation of HDAC6 is essential for supporting protein degradation pathways that prevent human disease.
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA. battini.2@wright.edu.
authors.forename: Vishnu Priya
authors.initials: VP
authors.lastname: Battini
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA. athanasios.bubulya@wright.edu.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Bubulya
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA. paula.bubulya@wright.edu.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Bubulya
mesh_terms: D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D017930:Genes, Reporter; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015778:Minor Histocompatibility Antigens; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; D012322:RNA Precursors; D034741:RNA, Small Interfering; C088203:SON protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases