Crosstalk of gene polymorphisms with RNA and protein phenotypic characteristics

doctoral thesis

• Title (croatian): Povezanost genskih polimorfizama s fenotipskim karakteristikama molekula RNA i proteina
• Author: Marina Rudan
• Mentor: Miroslav Radman (mentor)
• Committee member: Biljana Balen (predsjednik povjerenstva)
• Committee member: Davor Zahradka (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2018, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 577 - Biochemistry. Molecular biology. Biophysics

Abstract

Both RNA and protein molecules can misfold into non-functional conformations. Since DNA is transcribed into RNA to direct the biosynthesis of proteins, functional cells require the maintenance of DNA, RNA and protein homeostasis. Here, it is explored whether DNA polymorphisms can impact upon RNA and protein conformation to the extent of displaying phenotypic changes. It has been found that this is a multifaceted process. Mutation-induced protein conformational changes can modify protein interactions and determine protein susceptibility to oxidation. Moreover, it was showed that deleterious mutations can be buffered at the transcript level with RNA chaperones (DEAD-box RNA helicases and cold shock proteins) acting as phenotypic suppressors of mutations and enhancing cellular fitness. These results also highlight the importance of mRNA quality control in eukaryotes and its potential to modulate cellular metabolic activity and lifespan. This research underscores the importance of studying systems-level crosstalk among DNA, RNA and protein maintenance, rather than studying individual processes separately.

Abstract (croatian)

Molekule RNA i proteini se mogu pogrešno smotati u nefunkcionalne konformacije. Budući da se za biosintezu proteina DNA prepisuje u RNA, funkcionalne stanice zahtijevaju održavanje homeostaze DNA, RNA i proteina. U ovom radu je istraženo mogu li DNA polimorfizmi utjecati na konformaciju molekule RNA i proteina, te rezultirati fenotipskim promjenama. Otkriveno je da je ovo iznimno složen proces, tijekom kojeg konformacijske promjene proteina izazvane mutacijama molekula DNA mogu modificirati interakcije proteina i odrediti njihovu osjetljivost na oksidaciju. Također, pokazano je da štetne mutacije mogu biti puferirane na razini transkripcije pomoću RNA šaperona (DEAD-box RNA helikaza i 'cold shock' proteina), koji djeluju kao fenotipski supresori mutacija i poboljšavaju stanični fitnes. Ovi rezultati naglašavaju značaj kontrole kvalitete mRNA u eukariotima i njen potencijal za modulaciju stanične metaboličke aktivnosti te životnog vijeka. Ovo istraživanje ističe važnost proučavanja cjelokupnog sustava DNA, RNA i proteina, te njihove međusobne komunikacije umjesto analize staničnih procesa pojedinačno.

• Keywords: polymorphism; carbonylation; RNA chaperones; mutation buffering; splicing; retrograde response
• Keywords (croatian): polimorfizam; karbonilacija; RNA šaperoni; puferiranje mutacija; RNA izrezivanje; retrogradni odgovor
• Language: english
• URN:NBN: urn:nbn:hr:217:625111
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2018-04-06 10:08:29