Tls1 regulates splicing of shelterin components to control telomeric heterochromatin assembly and telomere length

Jiyong Wang, Xavier Tadeo, Haitong Hou, Stuart Andrews, James J. Moresco, John R. Yates, Peter L. Nagy, Songtao Jia

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11419-11432
Number of pages14
JournalNucleic acids research
Volume42
Issue number18
DOIs
StatePublished - Oct 13 2014

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Tls1 regulates splicing of shelterin components to control telomeric heterochromatin assembly and telomere length'. Together they form a unique fingerprint.

  • Cite this