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Research In The Function And Mechanism Of SirT1 Involved In Regulating Protein Translation

Posted on:2016-10-25Degree:DoctorType:Dissertation
Country:ChinaCandidate:P P ShanFull Text:PDF
GTID:1360330482958430Subject:Biomedicine
Abstract/Summary:PDF Full Text Request
Global repression of protein synthesis is a common response to stress conditions.Eukaryotic gene expression can be modulated at different levels including DNA transcription,mRNA posttranscriptional modification and translation initiation,these process are carefully tuned to match nutritional conditions.In eukaryotes,the mRNA transcribed in the nucleus must be exported into the cytoplasm for translation and the poly(A)-tail is important for mRNA export and translation.Pathways limiting mRNA export may be an effective way to rapid attenuation of general expression under stress conditions.Here we demonstrated that SirT1,the NAD-dependent deacetylase is required for a rapid shut off of mRNA export and translation under starvation.SirT1 associates and deacetylates poly(A)-mRNA binding protein PABP1,alters its intracellular localization,and attenuates its function in regulating poly(A)-mRNA export and translation initiation.Elimination of PABP1 K95 acetylation results in defective poly(A)-mRNA export and a significant reduction of cell growth and migration.Moreover,SirT1 inhibits translation during mitosis by disturbing PABP1 association with mRNA and translation factor eIF4G.Furthermore,SirT1 regulates PABP1 function through a phosphorylation-dependent mechanism.Here we demonstrated that SirT1,which acts as a master sensor of energy fluctuation,participated in regulating poly(A)mRNA shuttle under energy starvation and mRNA translation of M phase via its deacetylase activity.SirT1 knockdown cells and knockout mouse embryonic fibroblasts could not fully cause nuclear retention of poly(A)mRNA under starved conditions which further confirmed the function of SirT1 involved in this process.These findings uncover a control mechanism how eukaryotic cells dynamically regulate translation,and provide mechanistic insights by which SirT1 shutoff global protein synthesis in coordinating the cellular stress response.
Keywords/Search Tags:SirT1, PABP1, poly(A) mRNA, glucose starvation, acetylation
PDF Full Text Request
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