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UNDERSTANDING MECHANISMS THAT COUPLE TRANSLATION ELONGATION AND MRNA DECAY

Chen, Ying-Hsin
http://rave.ohiolink.edu/etdc/view?acc_num=case1522684403630693

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
mRNA is a unique molecule that is the product of transcription and the substrate for translation, two processes that are critical for regulating gene expression in all cells. Its abundance is determined by the balance between mRNA synthesis and decay. Once mRNA is exported to the cytoplasm, mRNA decay is a key regulator of mRNA levels. In eukaryotic cells, the major mRNA decay pathway is initiated by the removal of 3’ polyA tail, followed by 5’ decapping and exonucleolytic digestion in a 5’ to 3’ direction. The ranslation status of mRNA is known to be tightly integrated with the control of mRNA decay. Our lab has recently identified that the transcripts with a higher incidence of optimal codons are more stable compared to those composed of non-optimal codons. In the current work, we focus on how translation elongation is coupled to mRNA decay. We demonstrate that codon-mediated decay is impacted by both the deadenylation and decapping steps. In addition, we identify novel roles of 4 decay factors, DHH1, POP2, NOT2, and NOT5, in discriminating between optimal and non-optimal mRNAs. The DEAD-box protein Dhh1p is a known regulator of mRNA decapping and has suggested roles in translational control. We demonstrate that Dhh1p is a sensor of codon optimality to specifically associate and destabilize non-optimal mRNA at the decapping step by interacting with slow ribosomes on transcripts. We next explored how deadenylation is accelerated on non-optimal mRNAs. CCR4-NOT is a conserved multisubunit complex that conducts the major deadenylation activity in all eukaryotes. First, we show that the depletion of POP2, NOT2 or NOT5 preferentially stabilizes non-optimal mRNA by decreasing the deadenylation rate of non-optimal mRNA in a translation dependent manner. Second, the MIF4G domain of Not1p is critical for connecting deadenylation and decapping machinery to modulate codonmediated mRNA decay. Together, these results suggest a model where multiple factors in the decay machinery cooperate to monitor ribosome movement and reinforce the degradation of non-optimal mRNAs.
Jeff Coller, Ph.D (Advisor)
Jo Ann Wise, Ph.D (Committee Chair)
Maria Hatzoglou, Ph.D (Committee Member)
Donny Licatalosi, Ph.D (Committee Member)
Ashleigh Schaffer, Ph.D (Committee Member)
119 p.
Biochemistry; Molecular Biology
Codon optimality; Codon-mediated decay; DHH1; deadenylation complex

Recommended Citations

Citations

  • Chen, Y.-H. (2018). UNDERSTANDING MECHANISMS THAT COUPLE TRANSLATION ELONGATION AND MRNA DECAY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1522684403630693

    APA Style (7th edition)

  • Chen, Ying-Hsin. UNDERSTANDING MECHANISMS THAT COUPLE TRANSLATION ELONGATION AND MRNA DECAY. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1522684403630693.

    MLA Style (8th edition)

  • Chen, Ying-Hsin. "UNDERSTANDING MECHANISMS THAT COUPLE TRANSLATION ELONGATION AND MRNA DECAY." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522684403630693

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.