title: Wig1 prevents cellular senescence by regulating p21 mRNA decay through control of RISC recruitment.
abstract: Premature senescence, a key strategy used to suppress carcinogenesis, can be driven by p53/p21 proteins in response to various stresses. Here, we demonstrate that Wig1 plays a critical role in this process through regulation of p21 mRNA stability. Wig1 controls the association of Argonaute2 (Ago2), a central component of the RNA-induced silencing complex (RISC), with target p21 mRNA via binding of the stem-loop structure near the microRNA (miRNA) target site. Depletion of Wig1 prohibited miRNA-mediated p21 mRNA decay and resulted in premature senescence. Wig1 plays an essential role in cell proliferation, as demonstrated in tumour xenografts in mice, and Wig1 and p21 mRNA levels are inversely correlated in human normal and cancer tissues. Together, our data indicate a novel role of Wig1 in RISC target accessibility, which is a key step in RNA-mediated gene silencing. In addition, these findings indicate that fine-tuning of p21 levels by Wig1 is essential for the prevention of cellular senescence.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Bong Cho
authors.initials: BC
authors.lastname: Kim
authors.forename: Hyung Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Choi
authors.forename: Dong-Kwan
authors.initials: DK
authors.lastname: Kim
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Ko
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D020871:RNA Stability / Q000502:physiology*; D016601:RNA-Binding Proteins; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D034743:RNA-Induced Silencing Complex; C436503:ZMAT3 protein, human