20.500.12556/RUL-182141 Vloga večvalentnih nukleotidnih zaporedij pri negativni povratni regulaciji proteinov z intrinzično neurejenimi regijami Role of multivalent nucleotide sequences in negative feedback regulation of proteins with intrinsically disordered regions Proteostaza je ključna za normalno delovanje celic, pri čemer imajo proteini z intrinzično neurejenimi regijami osrednjo vlogo v signalizaciji in regulaciji, hkrati pa so nagnjeni k tvorbi toksičnih agregatov, povezanih z nevrodegenerativnimi boleznimi. Nedavno opisan interstazni mehanizem kaže, da GA-bogate multivalentne mRNA uravnavajo raven intrinzično neurejenih proteinov prek zadrževanja v jedrnih biomolekularnih kondenzatih. V magistrskem delu preučujemo, ali se interstazi podobna načela razširjajo na druge tipe multivalence in ali multivalenca predstavlja splošno organizacijsko načelo regulacije proteostaze na ravni transkriptoma. Razvili smo celovit računalniški pristop za identifikacijo multivalenčnih regij v CDS, 3′UTR in intronih človeških mRNA ter njihovo povezovanje z večplastnimi strukturnimi in funkcijskimi podatki. Na ravni transkriptoma smo pokazali, da multivalentne regije tvorijo pozicijsko specifične gruče in da njihovi vzorci v CDS statistično korelirajo z vzorci v nekodirajočih odsekih, kar podpira obstoj koordiniranega regulatornega jezika RNA. Skupine multivalenčnih regij smo razvrstili glede na niz strukturnih in funkcijskih značilnosti ter identificirali kandidate, ki so potencialno funkcionalno povezani z regulacijo proteostaze in biomolekularnimi kondenzati. Na podlagi rezultatov sklepamo, da je RNA multivalenca organizirana in funkcionalno pomembna lastnost, ki razširja koncept interstaze na širši spekter motivov ter prispeva k finemu uravnavanju homeostaze prek kompleksnega regulatornega jezika RNA. Proteostasis is essential for normal cellular function, with proteins containing intrinsically disordered regions playing a central role in signalling and regulation, while being prone to forming toxic aggregates associated with neurodegenerative diseases. The recently described interstasis mechanism shows that GA-rich multivalent mRNAs regulate the levels of intrinsically disordered proteins through sequestration in nuclear biomolecular condensates. In this master's thesis, we investigate whether interstasis-like principles extend to other types of multivalency and whether multivalency represents a general organisational principle for proteostasis regulation at the transcriptome level. We developed a comprehensive computational approach to identify multivalent regions in the CDS, 3′UTR, and introns of human mRNAs and integrated them with multilayered structural and functional data. At the transcriptome-wide level, we demonstrated that multivalent regions form position-specific clusters and that their patterns in CDS statistically correlate with patterns in non-coding regions, supporting the existence of a coordinated RNA regulatory language. We classified groups of multivalent regions based on sets of structural and functional features and identified candidates potentially linked to proteostasis regulation and biomolecular condensates. Based on the results, we conclude that RNA multivalency is an organised and functionally significant feature that extends the interstasis concept to a broader spectrum of motifs and contributes to fine-tuned homeostasis regulation via a complex RNA regulatory language. proteostaza interstaza multivalenca intrinzično neurejene regije biomolekularni kondenzati mRNA LLPS posttranskripcijska regulacija proteostasis interstasis multivalency intrinsically disordered regions biomolecular condensates mRNA LLPS post-transcriptional regulation true false false Slovenski jezik Angleški jezik Magistrsko delo/naloga 2026-04-25 07:16:00 2026-04-25 07:16:11 2026-05-04 14:13:24 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 279407 276943875 57341.pdf 57341.pdf 1 C6F60DD8DE73D210267C765E191A0DBD cc9c0f37877664a7e70fec497704a6b00add366010393d274b6a23d92710734e 9dfdbf0c-4065-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=233115 Biotehniška fakulteta 0 0 0