Stress-induced nuclear condensation of NELF drives transcriptional downregulation

Mol Cell. 2021 Mar 4;81(5):1013-1026.e11. doi: 10.1016/j.molcel.2021.01.016. Epub 2021 Feb 5.

Abstract

In response to stress, human cells coordinately downregulate transcription and translation of housekeeping genes. To downregulate transcription, the negative elongation factor (NELF) is recruited to gene promoters impairing RNA polymerase II elongation. Here we report that NELF rapidly forms nuclear condensates upon stress in human cells. Condensate formation requires NELF dephosphorylation and SUMOylation induced by stress. The intrinsically disordered region (IDR) in NELFA is necessary for nuclear NELF condensation and can be functionally replaced by the IDR of FUS or EWSR1 protein. We find that biomolecular condensation facilitates enhanced recruitment of NELF to promoters upon stress to drive transcriptional downregulation. Importantly, NELF condensation is required for cellular viability under stressful conditions. We propose that stress-induced NELF condensates reported here are nuclear counterparts of cytosolic stress granules. These two stress-inducible condensates may drive the coordinated downregulation of transcription and translation, likely forming a critical node of the stress survival strategy.

Keywords: CDK9; RNA polymerase II; SUMO; heat shock; negative elongation factor (NELF); pausing; phase separation; proteostasis; transcriptional condensates; transcriptional stress response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / metabolism
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Clone Cells
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism
  • Genes, Reporter
  • HEK293 Cells
  • HeLa Cells
  • Heat-Shock Response / genetics*
  • Humans
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / genetics*
  • Intrinsically Disordered Proteins / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Phosphorylation
  • Positive Transcriptional Elongation Factor B / genetics
  • Positive Transcriptional Elongation Factor B / metabolism
  • Promoter Regions, Genetic
  • Protein Processing, Post-Translational*
  • RNA Polymerase II / genetics*
  • RNA Polymerase II / metabolism
  • Red Fluorescent Protein
  • Signal Transduction
  • Stress, Physiological
  • Sumoylation
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptional Elongation Factors / chemistry
  • Transcriptional Elongation Factors / genetics*
  • Transcriptional Elongation Factors / metabolism

Substances

  • Chromatin
  • Intrinsically Disordered Proteins
  • Luminescent Proteins
  • NELFA protein, human
  • Transcription Factors
  • Transcriptional Elongation Factors
  • Aminoacyltransferases
  • ZNF451 protein, human
  • Positive Transcriptional Elongation Factor B
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
  • RNA Polymerase II