TOR complex 2 contributes to regulation of gene expression via inhibiting Gcn5 recruitment to subtelomeric and DNA replication stress genes

PLoS Genet. 2022 Feb 14;18(2):e1010061. doi: 10.1371/journal.pgen.1010061. eCollection 2022 Feb.

Abstract

The fission yeast TOR complex 2 (TORC2) is required for gene silencing at subtelomeric regions and for the induction of gene transcription in response to DNA replication stress. Thus, TORC2 affects transcription regulation both negatively and positively. Whether these two TORC2-dependent functions share a common molecular mechanism is currently unknown. Here, we show that Gad8 physically interacts with proteins that regulate transcription, including subunits of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex and the BET bromodomain protein Bdf2. We demonstrate that in the absence of TORC2, Gcn5, the histone acetyltransferase subunit of SAGA, accumulates at subtelomeric genes and at non-induced promoters of DNA replication genes. Remarkably, the loss of Gcn5 in TORC2 mutant cells restores gene silencing as well as transcriptional induction in response to DNA replication stress. Loss of Bdf2 alleviates excess of Gcn5 binding in TORC2 mutant cells and also rescues the aberrant regulation of transcription in these cells. Furthermore, the loss of either SAGA or Bdf2 suppresses the sensitivity of TORC2 mutant cells to a variety of stresses, including DNA replication, DNA damage, temperature and nutrient stresses. We suggest a role of TORC2 in transcriptional regulation that is critical for gene silencing and gene induction in response to stress and involves the binding of Gcn5 to the chromatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • DNA Replication / genetics
  • Fungal Proteins / genetics
  • Heterochromatin / metabolism
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / genetics
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Schizosaccharomyces pombe Proteins* / genetics
  • Schizosaccharomyces* / genetics

Substances

  • Fungal Proteins
  • Heterochromatin
  • Saccharomyces cerevisiae Proteins
  • Schizosaccharomyces pombe Proteins
  • Acetyltransferases
  • Gcn5 protein, S pombe
  • Histone Acetyltransferases
  • Mechanistic Target of Rapamycin Complex 2

Grants and funding

This research was supported by grants to R.W. from the Open University of Israel (grant 31054) and the Israel Science Foundation (grant 502/21). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.