TORC2 coordinates MBF-dependent transcription and restrains oxidative stress responses during DNA replication stress in fission yeast

TL;DR

This study shows how TORC2 helps cells respond to DNA replication stress by regulating gene activity and preventing unnecessary stress responses in fission yeast.

Contribution

The study reveals TORC2's dual role in regulating MBF-dependent transcription and suppressing oxidative stress responses during DNA replication stress.

Findings

TORC2 is necessary for RNA polymerase II accumulation at MBF promoters during replication stress.

TORC2-deficient cells show abnormal elongating RNA polymerase II accumulation at MBF coding regions.

TORC2-deficient cells upregulate oxidative stress genes and accumulate reactive oxygen species during replication stress.

Abstract

The target of rapamycin (TOR) kinase is a core component of two evolutionarily conserved complexes, TORC1 and TORC2, which regulate growth, metabolism, and stress responses. In Schizosaccharomyces pombe, TORC2 is dispensable for proliferation under optimal conditions but is essential for survival and adaptation to a variety of stress conditions, including DNA damage and replication stress. The MluI-binding factor (MBF) transcription complex regulates G1/S progression and the DNA replication stress response. Previously, we demonstrated that TORC2–Gad8 is required for the upregulation of MBF-dependent gene transcription in response to replication stress. Here, we show that in response to replication stress, TORC2 is necessary for the accumulation of the initiating form of RNA polymerase II (Pol II) at MBF promoters. In contrast, the elongating form of Pol II aberrantly accumulates at MBF coding regions in TORC2-deficient cells under both induced and noninduced conditions, suggesting a defect in balancing Pol II initiation and elongation that leads to impaired MBF gene induction. Unexpectedly, TORC2-deficient cells also exhibit aberrant upregulation of stress-activated genes during replication stress, including a distinct subset of Pap1-dependent oxidative stress genes. Consistent with this, TORC2 mutant cells accumulate reactive oxygen species in response to replication stress. Together, our findings suggest that TORC2 is required to ensure proper upregulation of MBF-dependent gene transcription during replication stress and to suppress inappropriate activation of oxidative stress response pathways.

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