Disruption of nucleocytoplasmic trafficking as a cellular senescence driver

Ji Hwan Park, Sung Jin Ryu, Byung Ju Kim, Hyun Ji Cho, Chi Hyun Park, Hyo Jei Claudia Choi, Eun Jin Jang, Eun Jae Yang, Jeong A. Hwang, Seung Hwa Woo, Jun Hyung Lee, Ji Hwan Park, Kyung Mi Choi, Young Yon Kwon, Cheol Koo Lee, Joon Tae Park, Sung Chun Cho, Yun Il Lee, Sung Bae Lee, Jeong A. HanKyung A. Cho, Min Sik Kim, Daehee Hwang, Young Sam Lee, Sang Chul Park

Research output: Contribution to journalArticlepeer-review


Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes.

Original languageEnglish (US)
Pages (from-to)1092-1108
Number of pages17
JournalExperimental and Molecular Medicine
Issue number6
StatePublished - Jun 2021
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


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