The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts

Felipe Beckedorff, Ezra Blumenthal, Lucas Ferreira daSilva, Yuki Aoi, Pradeep Reddy Cingaram, Jingyin Yue, Anda Zhang, Sadat Dokaneheifard, Monica Guiselle Valencia, Gabriel Gaidosh, Ali Shilatifard, Ramin Shiekhattar*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Transcription by RNA polymerase II (RNAPII) is pervasive in the human genome. However, the mechanisms controlling transcription at promoters and enhancers remain enigmatic. Here, we demonstrate that Integrator subunit 11 (INTS11), the catalytic subunit of the Integrator complex, regulates transcription at these loci through its endonuclease activity. Promoters of genes require INTS11 to cleave nascent transcripts associated with paused RNAPII and induce their premature termination in the proximity of the +1 nucleosome. The turnover of RNAPII permits the subsequent recruitment of an elongation-competent RNAPII complex, leading to productive elongation. In contrast, enhancers require INTS11 catalysis not to evict paused RNAPII but rather to terminate enhancer RNA transcription beyond the +1 nucleosome. These findings are supported by the differential occupancy of negative elongation factor (NELF), SPT5, and tyrosine-1-phosphorylated RNAPII. This study elucidates the role of Integrator in mediating transcriptional elongation at human promoters through the endonucleolytic cleavage of nascent transcripts and the dynamic turnover of RNAPII.

Original languageEnglish (US)
Article number107917
JournalCell reports
Volume32
Issue number3
DOIs
StatePublished - Jul 21 2020

Keywords

  • elongation
  • enhancers
  • integrator
  • pause-release
  • promoters
  • RNA polymerase II
  • RNA processing
  • termination
  • transcription
  • traveling ratio

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Beckedorff, F., Blumenthal, E., daSilva, L. F., Aoi, Y., Cingaram, P. R., Yue, J., Zhang, A., Dokaneheifard, S., Valencia, M. G., Gaidosh, G., Shilatifard, A., & Shiekhattar, R. (2020). The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts. Cell reports, 32(3), [107917]. https://doi.org/10.1016/j.celrep.2020.107917