{"id":4919,"date":"2020-01-07T19:09:39","date_gmt":"2020-01-07T10:09:39","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=4919"},"modified":"2020-01-07T19:09:39","modified_gmt":"2020-01-07T10:09:39","slug":"gene-expression-regulated-by-rna-stability","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=4919","title":{"rendered":"Gene expression regulated by RNA stability"},"content":{"rendered":"

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One of the first discoveries of gene expression mediated by controlling messenger RNA (mRNA) stability is autoregulation of tubulin synthesis. In this regulatory process, the concentration of tubulin subunits modulates the stability of the mRNAs from which they are translated (1<\/em><\/a>,\u00a02<\/em><\/a>). In the 1980s it was found that only translated tubulin mRNAs are autoregulated (3<\/em><\/a>) and that translation had to continue through at least 41 amino acids (4<\/em><\/a>). This is enough for the nascent tubulin polypeptide to emerge from the ribosome (5<\/em><\/a>). Later work established that when the tubulin subunit pool is high, the first four amino acids (Met-Arg-Glu-Ile, MREI) emerging during nascent tubulin translation serve as a regulatory tag. Recognition of this tag promoted the degradation of the translating tubulin mRNA (4<\/em><\/a>,\u00a06<\/em><\/a>\u20138<\/em><\/a>). More than 30 years later, on page 100 of this issue, Lin\u00a0et al.<\/em>\u00a0(9<\/em><\/a>) identify tetratricopeptide repeat protein 5 (TTC5) as the regulator that binds to nascent tubulin polypeptides.<\/p>\n

With the exception of a high-resolution confirmation that an elevated pool of tubulin subunits selectively represses tubulin synthesis (8<\/em><\/a>), no progress toward understanding the autoregulation of tubulin expression was made since 1988. The most attractive model for how the pool size of tubulin subunits could trigger rapid mRNA degradation to suppress new tubulin synthesis was that it was the tubulin \u03b1\/\u03b2 dimer, the unit that assembles into microtubules, that cotranslationally bound to the MREI tetrapeptide. Lin\u00a0et al.<\/em>\u00a0disprove this model. They use mass spectrometry and in vitro translation of an mRNA encoding the first 94 amino acids of \u03b2-tubulin to identify TTC5 as the protein that recognizes the nascent \u03b2-tubulin MREI tetrapeptide in complex with the large ribosomal subunit.<\/p>\n

\u03b1- and \u03b2-tubulin form a heterodimer that serves as the building block for microtubule polymers, the tracks along which cargoes are moved by dynein and kinesin family motors. During cell duplication, microtubule-directed trafficking is essential for delivery to each daughter cell of a complete set of chromosomes. By inactivating both maternal and paternal copies of the gene encoding TTC5, Lin\u00a0et al.<\/em>\u00a0demonstrate that tubulin autoregulation is essential for maintaining faithful chromosome segregation, with a modest increase in chromosome segregation errors in the absence of TTC5. Errors in chromosome inheritance are key drivers of tumorigenesis, so maintenance of the genome is important (10<\/em><\/a>). However, Lin\u00a0et al.<\/em>\u00a0have determined that cells with inactivated tubulin autoregulation are viable and can continue to survive and duplicate. This is unexpected because disruption of autoregulation would be predicted to yield runaway tubulin synthesis, which in turn should have severely disrupted microtubule assembly dynamics and function. Perhaps additional factors are involved, the activities of which might compensate, to some extent, for the lack of TTC5 activity.<\/p>\n

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