AntisenseRNA mediated gene regulation via double stranded RNA formation
by Cesur Ivo Coban
Date of Examination:2022-03-01
Date of issue:2023-03-01
Advisor:Prof. Dr. Heike Krebber
Referee:Prof. Dr. Heike Krebber
Referee:Prof. Dr. Jörg Großhans
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EnglishThe flow of genetic information in eukaryotic cells is established through transcription from the nuclear DNA into messenger (m)RNA, which travels into the cytoplasm for translation into proteins, the functional units of cells. With the discovery of the manifold existence of long non-coding (lnc)RNAs, which amounts exceed the ones of mRNAs, the established dogma (DNA:RNA:Protein) has been challenged. Still, the general functionality of most lncRNAs is debated, and mostly individual functions have been unraveled so far. Especially, antisense (as)RNAs exist in a high number. Although the majority of asRNAs is degraded by translation associated nonsense-mediated decay and the cytoplasmic exonuclease Xrn1, their attributed functions in S. cerevisiae are so far restricted to the nucleus and transcriptional regulation, leaving their journey into the cytoplasm out of sight. Here, we identify a new mechanism, in which asRNAs accelerate the export of their mRNA counterparts by forming double stranded RNAs (dsRNA). dsRNAs have a higher affinity and capacity for the nuclear export heterodimer Mex67-Mtr2 than single stranded mRNAs, which results in a faster export. This preferential export represents a major and essential advantage for cells to adapt to new necessities through the rapid establishment of new gene expression programs. Furthermore, we unravel a specific function of the asRNA SUT802 in translation inhibition of its corresponding mRNA FRE5. SUT802 recruits the translational repressor Hek2 to the SUT802-FRE5 dsRNA under repressing conditions. Thereby, it enables the possibility of even tighter regulation of gene expression in iron homeostasis. Together, these unraveled novel mechanisms highlight the multifunctionality of asRNA in modulating mRNA gene expression.
Keywords: RNA; LncRNA; Nucleocytoplasmic export