Repression of the SUMO-specific protease Senp1 induces p53-dependent premature senescence in normal human fibroblasts.
The proliferative lifespan of normal somatic human cells in culture terminates in a permanent growth-arrested state known as replicative senescence. In this study, we show that RNA interference-mediated repression of the genes encoding the small ubiquitin-related modifier (SUMO)-specific proteases, Senp1, Senp2, and Senp7, induced low passage primary human fibroblasts to senesce rapidly. Following Senp1 repression, we observed a global increase in sumoylated proteins and in the number and size of nuclear SUMO-containing promyelocytic leukemia (PML) bodies. SUMO/PML bodies also increased during replicative senescence. p53 transcriptional activity was enhanced towards known p53 target genes following repression of Senp1, and inhibition of p53 function prevented senescence after Senp1 repression. These data indicate that Senp1 repression induces p53-mediated premature senescence and that SUMO proteases may thus be required for proliferation of normal human cells.
Yates
Kristin E
KE
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
Korbel
Gregory A
GA
Shtutman
Michael
M
Roninson
Igor B
IB
DiMaio
Daniel
D
D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004794:Enzyme Repression / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D034622:RNA Interference / Q000502:physiology; D025842:SUMO-1 Protein / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human