title: Tls1 regulates splicing of shelterin components to control telomeric heterochromatin assembly and telomere length.
abstract: Heterochromatin preferentially forms at repetitive DNA elements through RNAi-mediated targeting of histone-modifying enzymes. It was proposed that splicing factors interact with the RNAi machinery or regulate the splicing of repeat transcripts to directly participate in heterochromatin assembly. Here, by screening the fission yeast deletion library, we comprehensively identified factors required for telomeric heterochromatin assembly, including a novel gene tls1+. Purification of Tls1 and mass spectrometry analysis of its interacting proteins show that Tls1 associates with the spliceosome subunit Brr2. RNA sequencing analysis shows that the splicing of a subset of mRNAs are affected in tls1Δ cells, including mRNAs of shelterin components rap1+ and poz1+. Importantly, replacing rap1+ and poz1+ with their cDNAs significantly alleviated heterochromatin defects of tls1Δ cells, suggesting that the missplicing of shelterin components is the cause of such defects, and that splicing factors regulate telomeric heterochromatin through the proper splicing of heterochromatin factors. In addition to its role in telomeric heterochromatin assembly, Tls1-mediated splicing of shelterin mRNAs also regulates telomere length. Given that its human homologue C9ORF78 also associates with the spliceosome and is overexpressed in multiple cancer cell lines, our results suggest that C9ORF78 overexpression might alter the proper splicing of genes during cancer progression.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Tadeo
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY, USA.
authors.forename: Haitong
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Andrews
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Nagy
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY, USA sj2274@columbia.edu.
authors.forename: Songtao
authors.initials: S
authors.lastname: Jia
mesh_terms: D006570:Heterochromatin / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017381:Spliceosomes / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006570:Heterochromatin; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D029702:Schizosaccharomyces pombe Proteins; D034501:Telomere-Binding Proteins; C000594510:Tls1 protein, S pombe