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생체시계유전자 mRNA 3′UTR에 결합하는 단백질에 의한 전사 후 조절이 일주기 리듬에 미치는 기전 규명

생체시계유전자 mRNA 3′UTR에 결합하는 단백질에 의한 전사 후 조절이 일주기 리듬에 미치는 기전 규명
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The mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Circadian mRNA oscillations are the main feature of core clock genes. Among them, period 2 (per2) and cryptochrme 1 (cry1) are key components in negative-feedback regulation, showing robust oscillation in both mRNA and protein, as well as their protein heterodimer actively translocate from cytosol to nucleus for the feedback inhibition. However, little is known about post-transcriptional regulation of these genes. During the course of degree, I have been focused on the role of 3′ untranslated region (UTR)-dependent mRNA decay involved in the regulation of circadian oscillation of per2 or cry1 mRNA. I could successfully identify both responsible cis-acting 3′UTR elements (CAEs) as binding flatforms and trans-acting factors (TAFs) as functional players for respective genes mRNA stability and degradation kinetics. Interestingly, during the circadian oscillations of per2 or cry1, cytoplasmic fraction of TAFs showed reciprocal expression profiles compared with respective mRNAs implying their action in cytoplasm. In addition, their peak amplitudes were modulated when TAFs were reduced by RNAi. Because circadian genes have been also found to have a physiological role in the cell cycle or the tumor suppression, elucidating precise molecular mechanism of these genes is important. This thesis on the regulation of per2 and cry1 proposes that post-transcriptional mRNA decay mediated by TAFs is a fine-tuned regulatory mechanism that includes dampening-down effects during circadian mRNA oscillations. The mRNA degradation control is a fundamental step in gene expression regulation. Eukaryotic mRNA degradation mechanisms including mRNA surveillance pathways such as nonsense-mediated mRNA decay (NMD), or nonstop decay (NSD) are mediated by cytoplasmic exosome which is a multi-ribonuclease complex. Exosome components and their interaction are well characterized in yeast. In this research, we speculated the functional protein associating with exosome and target mRNAs. Guanosine triphosphates binding protein 1 (GTPBP1) was identified as one of proteins bound to rat Aanat mRNA, and interestingly it showed nocturnal expression profile in pineal gland. For other class of mRNAs, like Periods or Tnf-α, GTPBP1 binding was also observed. Overexpression of GTPBP1 accelerates target mRNA decay and reduction by RNA interference (RNAi) stabilizes them. It has putative GTP binding domain like other G-proteins or ski7p which is well known core factor of exosome mediated mRNA decay in yeast. Experiments to examine protein interaction or mRNA decay using guanine-nucleotide analogues showed mRNA degradation mechanism mediated by GTPBP1 is modulated by its GTPase activity. Moreover, in comparison with wildtype mice, GTPBP1 knockout model showed not only enhanced level of Aanat mRNA in pineal gland during night but also retarded degradation of cytokine mRNA, such as Tnf-α in lipopolysaccharide (LPS) induced splenocytes. This thesis on the regulation of mRNA degradation suggest that GTPBP1 should be a key regulator and adaptor for exosome mediated mRNA degradation.
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