LMO7-mediated POLR2A degradation promotes cellular senescence through the MDM4/p53/p21 axis
Chutong Lai1,2, Wen Fu1,2, Jiaxin Liu1,2
1Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China.
Cell Death & Disease
|March 28, 2026
Summary
The largest subunit of RNA polymerase II (POLR2A) acts as a guardian against cellular senescence. Its degradation, mediated by LMO7, drives senescence via the MDM4/p53/p21 pathway.
Area of Science:
- Molecular Biology
- Cellular Biology
- Aging Research
Background:
- RNA polymerase II subunit A (POLR2A) is crucial for gene expression.
- Regulation of POLR2A expression and function is vital.
- Cellular senescence is a key process in aging.
Purpose of the Study:
- To investigate the role of POLR2A in cellular senescence.
- To elucidate the molecular mechanisms underlying POLR2A regulation during senescence.
Main Methods:
- CRISPR activation (CRISPRa) technology
- RNA sequencing (RNA-seq)
- Immunoprecipitation assays
- Western blotting
- p53/p21 pathway analysis
Main Results:
- POLR2A expression declines in senescent cells and aging tissues.
- POLR2A depletion induces senescence; its activation alleviates senescence.
- Senescence induced by POLR2A is p53-dependent, involving the p53/p21 pathway.
- MDM4 mediates p53 upregulation upon POLR2A knockdown.
- LMO7 promotes POLR2A ubiquitination and degradation in senescent cells.
Conclusions:
- LMO7-mediated POLR2A degradation drives cellular senescence.
- The MDM4/p53/p21 axis is a key pathway in POLR2A-induced senescence.
- POLR2A is a critical guardian against cellular senescence.
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