Molekulární principy reiniciace u savců

• Název práce v češtině: Molekulární principy reiniciace u savců
• Název v anglickém jazyce: Molecular principles of translation reinitiation in mammals
• Klíčová slova: reiniciace, ATF4, ribosome, translační kontrola
• Klíčová slova anglicky: reinitiation, ATF4, ribosome, translational control
• Akademický rok vypsání: 2018/2019
• Typ práce: disertační práce
• Jazyk práce: čeština
• Ústav: Katedra genetiky a mikrobiologie (31-140)
• Vedoucí / školitel: RNDr. Leoš Valášek, DSc., Ph.D.
• Řešitel: skrytý - zadáno vedoucím/školitelem
• Datum přihlášení: 29.10.2018
• Datum zadání: 29.10.2018

Předběžná náplň práce

Studium mechanismu regulace translace u stresového transcripčního faktoru ATF4 u člověka.

Předběžná náplň práce v anglickém jazyce

The widespread prevalence of short upstream ORFs (uORFs) in mammalian transcriptomes (up to 50%) suggests that reinitiation (REI) after translation of a short ORF represents a comprehensive cis-regulatory function in translational control of eukaryotic gene expression. Indeed, several examples of aberrant protein expression leading to pathophysiological mechanisms in the etiology of human diseases that are connected to defective uORF-mediated translational control have already been described. However, a very few of these studies provided sufficient molecular details of how these short uORFs operate under normal vs. stress conditions, not talking about what goes wrong mechanistically during the observed pathologies.
The integrated stress response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. In acute/transient ER stress, global protein synthesis is shut down whereas translation of several short uORF-regulated mRNAs is upregulated to adapt cells to stress. If the stress does not persist for too long, the adaptation period is followed by normalization of protein synthesis signifying recovery from stress during which expression form these regulatory short uORF-containing mRNAs is ceased. We recently reported a dramatically different response occurring during chronic ER stress, which may eventually lead to a pathological state (1). This chronic ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. The program includes PERK-dependent switching to an eIF4F/eIF2B-independent, eIF3-dependent translation initiation mechanism, resulting in partial, but not complete, translational recovery, which, together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of transcriptional and translational reprogramming prevents ER dysfunction and inhibits "foamy cell" development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction.
The future work aims at understanding molecular principles of the surprisingly critical role of eIF3 in chronic ER stress. How does it ensure that only short uORF-containing mRNAs are loaded onto the ribosome and translated, is there any direct functional “contact” between eIF3 and these uORFs (there is some indication that it could be (2)), how does this regulatory mechanism eliminates the need for otherwise critical eIFs such as eIF4F and eIF2B, etc.? These and many other questions are waiting for our new PhD student-candidate, Bc. Anna Smirnova, to answer.