Targeting Spt5-Pol II by Small-Molecule Inhibitors Uncouples Distinct Activities and Reveals Additional Regulatory Roles

Anat Bahat, Or Lahav, Alexander Plotnikov, Dena Leshkowitz, Rivka Dikstein

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Spt5 is a conserved and essential transcription elongation factor that promotes promoter-proximal pausing, promoter escape, elongation, and mRNA processing. Spt5 plays specific roles in the transcription of inflammation and stress-induced genes and tri-nucleotide expanded-repeat genes involved in inherited neurological pathologies. Here, we report the identification of Spt5-Pol II small-molecule inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on promoter-proximal pausing, NF-κB activation, and expanded-repeat huntingtin gene transcription. Using SPIs, we identified Spt5 target genes that responded with profoundly diverse kinetics. SPIs uncovered the regulatory role of Spt5 in metabolism via GDF15, a food intake- and body weight-inhibitory hormone. SPIs further unveiled a role for Spt5 in promoting the 3′ end processing of histone genes. While several SPIs affect all Spt5 functions, a few inhibit a single one, implying uncoupling and selective targeting of Spt5 activities. SPIs expand the understanding of Spt5-Pol II functions and are potential drugs against metabolic and neurodegenerative diseases.

Original languageEnglish
Pages (from-to)617-631.e4
JournalMolecular Cell
Volume76
Issue number4
DOIs
StatePublished - 21 Nov 2019
Externally publishedYes

Keywords

  • DSIF
  • GDF15
  • Huntington disease
  • NF-κB
  • Pol II
  • SPI
  • Spt4
  • Spt5
  • histone genes termination
  • promoter-proximal pausing

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