Reduced Geminin levels promote cellular senescence

• Published in: Mechanisms of ageing and development 2013-01, Vol.134 (1-2), p.10-23
• Main Authors: Iliou, Maria S., Kotantaki, Panorea, Karamitros, Dimitris, Spella, Magda, Taraviras, Stavros, Lygerou, Zoi
• Format: Article
• Language: English
• Subjects: Animals; Cdt1; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Cellular Senescence - physiology; DNA damage; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; G1 Phase - physiology; Geminin; Gene Expression Regulation - physiology; HeLa Cells; Humans; Mice; Oxidative stress; S Phase - physiology; Senescence; SMN Complex Proteins - biosynthesis; SMN Complex Proteins - genetics
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2012.10.001

► Cells must strictly regulate entry to senescence and couple it with cell cycle control. ► Down-regulation of Geminin, a central cell cycle regulator, temporally precedes and can promote entry to senescence. ► Geminin is functionally implicated in the passage from the proliferating to the senescent state. ► Geminin may provide a functional link between the control of DNA replication and senescence. ► Geminin targeted down-regulation could be used to promote senescence. Cellular senescence is a permanent out-of-cycle state regulated by molecular circuits acting during the G1 phase of the cell cycle. Cdt1 is a central regulator of DNA replication licensing acting during the G1 phase and it is negatively controlled by Geminin. Here, we characterize the cell cycle expression pattern of Cdt1 and Geminin during successive passages of primary fibroblasts and compare it to tumour-derived cell lines. Cdt1 and Geminin are strictly expressed in distinct subpopulations of young fibroblasts, similarly to cancer cells, with Geminin accumulating shortly after the onset of S phase. Cdt1 and Geminin are down-regulated when primary human and mouse fibroblasts undergo replicative or stress-induced senescence. RNAi-mediated Geminin knock-down in human cells enhances the appearance of phenotypic and molecular features of senescence. Mouse embryonic fibroblasts heterozygous for Geminin exhibit accelerated senescence compared to control fibroblasts. In contrast, ectopic expression of Geminin in mouse embryonic fibroblasts delays the appearance of the senescent phenotype. Taken together, our data suggest that changes in Geminin expression levels affect the establishment of senescence pathways.