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Peer-reviewedCC BY-NC-NDGenome biology

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

  • Shunyi Li1,2
  • Beituo Qian1,2
  • Feng Qiu1,2
  • Yongjia Duan1
  • Rirong Hu1,2
  • Jihong Cui1
  • Wanjin Li3,4
  • Yanshan Fang5,6
6 affiliations
  1. 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
  2. 2University of Chinese Academy of Sciences, Beijing, 100049, China.
  3. 3Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China. [email protected].
  4. 4University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  5. 5Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China. [email protected].
  6. 6University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{li2026cdc5l,
  title = {{CDC5L functions as a transcriptional repressor to safeguard against overactive stress response and promote survival.}},
  author = {Shunyi Li and Beituo Qian and Feng Qiu and Yongjia Duan and Rirong Hu and Jihong Cui and Wanjin Li and Yanshan Fang},
  journal = {Genome biology},
  year = {2026},
  month = aug,
  doi = {10.1186/s13059-026-04224-6},
  url = {https://europepmc.org/article/MED/42972438},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - CDC5L functions as a transcriptional repressor to safeguard against overactive stress response and promote survival.
AU  - Shunyi Li
AU  - Beituo Qian
AU  - Feng Qiu
AU  - Yongjia Duan
AU  - Rirong Hu
AU  - Jihong Cui
AU  - Wanjin Li
AU  - Yanshan Fang
PY  - 2026
DA  - 2026/08/01
JO  - Genome biology
DO  - 10.1186/s13059-026-04224-6
UR  - https://europepmc.org/article/MED/42972438
AB  - 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.
SN  - 1474-7596
SN  - 1474-760X
ER  -