Integrator subunit 4 is a ‘Symplekin-like’ scaffold that associates with INTS9/11 to form the Integrator cleavage module

Todd R. Albrecht, Sergey P. Shevtsov, Yixuan Wu, Lauren G. Mascibroda, Natoya J. Peart, Kai Lieh Huang, Iain A. Sawyer, Liang Tong, Miroslav Dundr, Eric J. Wagner

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Integrator (INT) is a transcriptional regulatory complex associated with RNA polymerase II that is required for the 3-end processing of both UsnRNAs and enhancer RNAs. Integrator subunits 9 (INTS9) and INTS11 constitute the catalytic core of INT and are paralogues of the cleavage and polyadenylation specificity factors CPSF100 and CPSF73. While CPSF73/100 are known to associate with a third protein called Symplekin, there is no paralog of Symplekin within INT raising the question of how INTS9/11 associate with the other INT subunits. Here, we have identified that INTS4 is a specific and conserved interaction partner of INTS9/11 that does not interact with either subunit individually. Although INTS4 has no significant homology with Symplekin, it possesses N-terminal HEAT repeats similar to Symplekin but also contains a -sheet rich C-terminal region, both of which are important to bind INTS9/11. We assess three functions of INT including UsnRNA 3-end processing, maintenance of Cajal body structural integrity, and formation of histone locus bodies to conclude that INTS4/9/11 are the most critical of the INT subunits for UsnRNA biogenesis. Altogether, these results indicate that INTS4/9/11 compose a heterotrimeric complex that likely represents the Integrator ‘cleavage module’ responsible for its endonucleolytic activity.

Original languageEnglish (US)
Pages (from-to)4241-4255
Number of pages15
JournalNucleic acids research
Volume46
Issue number8
DOIs
StatePublished - 2018

ASJC Scopus subject areas

  • Genetics

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