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 Wagner

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6 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 - Jan 1 2018

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ASJC Scopus subject areas

  • Genetics

Cite this

Albrecht, T. R., Shevtsov, S. P., Wu, Y., Mascibroda, L. G., Peart, N. J., Huang, K-L., Sawyer, I. A., Tong, L., Dundr, M., & Wagner, E. (2018). Integrator subunit 4 is a ‘Symplekin-like’ scaffold that associates with INTS9/11 to form the Integrator cleavage module. Nucleic Acids Research, 46(8), 4241-4255. https://doi.org/10.1093/nar/gky100