PES1 Repression Triggers Ribosomal Biogenesis Impairment and Cellular Senescence Through p53 Pathway Activation
10.16476/j.pibb.2025.0005
- VernacularTitle:PES1表达缺陷介导核糖体生成抑制并通过激活p53信号诱导细胞衰老
- Author:
Chang-Jian ZHANG
1
;
Yu-Fang LI
1
;
Feng-Yun WU
1
;
Rui JIN
1
;
Chang NIU
2
;
Qi-Nong YE
1
;
Long CHENG
3
Author Information
1. Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China
2. College of Life Sciences, Capital Normal University, Beijing 100069, China
3. Beijing Institute of Geriatrics, National Health Commission, Beijing Hospital, Beijing 100005, China
- Publication Type:Journal Article
- Keywords:
PES1;
cellular senescence;
ribosomal biogenesis;
p53
- From:
Progress in Biochemistry and Biophysics
2025;52(7):1853-1865
- CountryChina
- Language:English
-
Abstract:
ObjectiveThe nucleolar protein PES1 (Pescadillo homolog 1) plays critical roles in ribosome biogenesis and cell cycle regulation, yet its involvement in cellular senescence remains poorly understood. This study aimed to comprehensively investigate the functional consequences of PES1 suppression in cellular senescence and elucidate the molecular mechanisms underlying its regulatory role. MethodsInitially, we assessed PES1 expression patterns in two distinct senescence models: replicative senescent mouse embryonic fibroblasts (MEFs) and doxorubicin-induced senescent human hepatocellular carcinoma HepG2 cells. Subsequently, PES1 expression was specifically downregulated using siRNA-mediated knockdown in these cell lines as well as additional relevant cell types. Cellular proliferation and senescence were assessed by EdU incorporation and SA-β-gal staining assays, respectively. The expression of senescence-associated proteins (p53, p21, and Rb) and SASP factors (IL-6, IL-1β, and IL-8) were analyzed by Western blot or qPCR. Furthermore, Northern blot and immunofluorescence were employed to evaluate pre-rRNA processing and nucleolar morphology. ResultsPES1 expression was significantly downregulated in senescent MEFs and HepG2 cells. PES1 knockdown resulted in decreased EdU-positive cells and increased SA‑β‑gal-positive cells, indicating proliferation inhibition and senescence induction. Mechanistically, PES1 suppression activated the p53-p21 pathway without affecting Rb expression, while upregulating IL-6, IL-1β, and IL-8 production. Notably, PES1 depletion impaired pre-rRNA maturation and induced nucleolar stress, as evidenced by aberrant nucleolar morphology. ConclusionOur findings demonstrate that PES1 deficiency triggers nucleolar stress and promotes p53-dependent (but Rb-independent) cellular senescence, highlighting its crucial role in maintaining nucleolar homeostasis and regulating senescence-associated pathways.
