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Background <p>Cells have evolved sophisticated molecular and cellular mechanisms to cope with stress. While these stress programs are vital, their overactivation as well as spurious activation in non-stress conditions must be prevented. The mechanisms enforcing this restraint remain unclear.</p> Results <p>Here, we report that depletion of <i>Cell Division Cycle 5 Like</i> (<i>CDC5L</i>) induces spontaneous stress granule (SG) assembly, and this effect is independent of its established functions in the cell cycle or the PRP19/CDC5L splicing complex. We find that knockdown of <i>CDC5L</i> increases the protein abundance of the stress kinase PERK, and this increase is sufficient to promote eIF2α hyperphosphorylation and trigger SG assembly. Mechanistically, CDC5L binds the <i>PERK</i> promoter via the DNA-binding domains and represses <i>PERK</i> expression. Integrative RNA-seq and ChIP-seq analyses further reveal a dual transcriptional function of CDC5L: it activates the transcription of cell-cycle related genes while repressing that of stress response genes. Consequently, <i>CDC5L</i> depletion leads to widespread upregulation of stress pathways, which elevates stress sensitivity, lowers stress tolerance, and reduces cell and animal survival under stressed conditions.</p> Conclusions <p>Our findings reveal a crucial role for CDC5L in transcriptional regulation of stress response pathways (e.g., the PERK–eIF2α–SG axis), which may precisely modulate gene expression and coordinate specific cellular programs—such as cell proliferation and stress adaptation—in response to changing conditions.</p>

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CDC5L functions as a transcriptional repressor to safeguard against overactive stress response and promote survival

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Shunyi Li,
  • Beituo Qian,
  • Feng Qiu,
  • Yongjia Duan,
  • Rirong Hu,
  • Jihong Cui,
  • Wanjin Li,
  • Yanshan Fang

摘要

Background

Cells have evolved sophisticated molecular and cellular mechanisms to cope with stress. While these stress programs are vital, their overactivation as well as spurious activation in non-stress conditions must be prevented. The mechanisms enforcing this restraint remain unclear.

Results

Here, we report that depletion of Cell Division Cycle 5 Like (CDC5L) induces spontaneous stress granule (SG) assembly, and this effect is independent of its established functions in the cell cycle or the PRP19/CDC5L splicing complex. We find that knockdown of CDC5L increases the protein abundance of the stress kinase PERK, and this increase is sufficient to promote eIF2α hyperphosphorylation and trigger SG assembly. Mechanistically, CDC5L binds the PERK promoter via the DNA-binding domains and represses PERK expression. Integrative RNA-seq and ChIP-seq analyses further reveal a dual transcriptional function of CDC5L: it activates the transcription of cell-cycle related genes while repressing that of stress response genes. Consequently, CDC5L depletion leads to widespread upregulation of stress pathways, which elevates stress sensitivity, lowers stress tolerance, and reduces cell and animal survival under stressed conditions.

Conclusions

Our findings reveal a crucial role for CDC5L in transcriptional regulation of stress response pathways (e.g., the PERK–eIF2α–SG axis), which may precisely modulate gene expression and coordinate specific cellular programs—such as cell proliferation and stress adaptation—in response to changing conditions.