[초청강연] Disruption of nucleocytoplasmic trafficking as a cellular senescence driver

Disruption of nucleocytoplasmic trafficking as a cellular senescence driver

Young-Sam Lee

Department of New Biology, DGIST, Daegu 42988, Korea

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.