The role of helicases Hmi1 and Irc3 in yeast mitochondrial DNA maintenance
Date
2024-05-16
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Abstract
Mitokonder on multifunktsionaalne rakuorganell, mille üheks olulisemaks ülesandeks on oksüdatiivne fosforüleerimine, mille tagab mitokondriaalne hingamisahel. Hingamisahel pannakse mitokondris kokku põhiliselt tuuma genoomi poolt sünteesitud valkudest, kuid väikene osa valke sünteesitakse ka mitokondri enda väikese genoomi poolt. Mitokondriaalse DNA säilitamine on oluline eukarüootse raku ellu jäämiseks ja ka väiksemad ümberkorraldused mitokondri genoomis viivad inimestel erinevate mitokondriaalsete haiguste tekkimiseni.
Pagaripärm S. cerevisiae on eriline mudelorganism, kuna suudab fermentatiivsel süsinikuallikal ellu jääda ka ainult osalise või täielikult puuduva mitokondriaalse DNA-ta. See võimaldab uurida erinevate valkude puudumise mõju mitokondriaalse DNA säilimisele. Üheks selliseks valkude grupiks on helikaasid, mis kasutavad erinevate nukleiinhapete modifitseerimiseks ja lahti sidumiseks ATP hüdrolüüsi energiat.
Käesolev doktoritöö keskendub kahe pärmi-spetsiifilise mitokondriaalse DNA helikaaside Hmi1 ja Irc3 funktsiooni uurimisele. Doktoritöö tulemused näitavad, et Irc3-laadsed helikaasid on olulised hargnenud DNA molekulide modifitseerimises, et vältida kahjustatud ja katki läinud DNA molekulide kuhjumist rakus, mis viiks aja jooksul mitokondriaalse DNA kadumiseni. Lisaks sellele on Irc3-laadse helikaasid tõenäoliselt olulised ka RNA metabolismis ja see funktsioon, võib mõjutada ka mitokondriaalse DNA säilimist.
Hmi1 helikaas on hädavajalik funktsionaalse mitokondriaalse genoomi säilimiseks S. cerevisiae rakkudes. Erinevalt paljudest teistest helikaasidest ei ole ATP hürdolüüs hädavajalik Hmi1 funktsioneerimiseks. Doktoritöö tulemused näitavad, et Hmi1 omab mitokondris nii ATP hüdrolüüsist sõltuvat kui ka sõltumatut funktsiooni.
Selle doktoritöö tulemused laiendavad meie arusaama mitokondriaalsete helikaaside mitmekülgsusest ja aitavad kaasa mitokondriaalse DNA säilimise komplekse süsteemi mõistmisele.
Mitochondrion is a multifunctional organelle best known for its role in oxidative phosphorylation through maintaining the respiratory chain. Although most of the proteins needed for the assembly of the respiratory chain are encoded by the nuclear genome, a handful of proteins are also encoded by small mitochondrial genome. Therefore, it is important to maintain the functional mitochondrial DNA, as its loss can lead to cell death. Furthermore, even small mitochondrial genome rearrangements have been associated with different human diseases. Some species, like baker’s yeast Saccharomyces cerevisiae, can survive without any or with nonfunctional mitochondrial DNA, making it a good model system for observing the effects on mtDNA integrity. One group of proteins required for mtDNA maintenance are helicases, which use ATP energy for unwinding different nucleic acid structures. The present thesis focuses on the function of mitochondrial DNA helicases Hmi1 and Irc3. The results show, that Irc3-like helicases are important for modifying the branched DNA molecules and preventing the accumulation of damaged and broken DNA molecules, which in time would lead to the loss of mitochondrial DNA. In addition, Irc3-like helicases also participate in RNA metabolism, a function that might also affect mtDNA maintenance. Hmi1 is a helicase essential for the maintenance of the functional mitochondrial genome of S. cerevisiae. Unlike most helicases, ATP hydrolysis is partially dispensable for the Hmi1 function. The results of this thesis indicate, that Hmi1 has ATP hydrolysis dependent and independent function in the cell. Collectively, the results of this thesis show how diverse are the mitochondrial helicases and give an insight into the complex system of maintaining the mitochondrial DNA.
Mitochondrion is a multifunctional organelle best known for its role in oxidative phosphorylation through maintaining the respiratory chain. Although most of the proteins needed for the assembly of the respiratory chain are encoded by the nuclear genome, a handful of proteins are also encoded by small mitochondrial genome. Therefore, it is important to maintain the functional mitochondrial DNA, as its loss can lead to cell death. Furthermore, even small mitochondrial genome rearrangements have been associated with different human diseases. Some species, like baker’s yeast Saccharomyces cerevisiae, can survive without any or with nonfunctional mitochondrial DNA, making it a good model system for observing the effects on mtDNA integrity. One group of proteins required for mtDNA maintenance are helicases, which use ATP energy for unwinding different nucleic acid structures. The present thesis focuses on the function of mitochondrial DNA helicases Hmi1 and Irc3. The results show, that Irc3-like helicases are important for modifying the branched DNA molecules and preventing the accumulation of damaged and broken DNA molecules, which in time would lead to the loss of mitochondrial DNA. In addition, Irc3-like helicases also participate in RNA metabolism, a function that might also affect mtDNA maintenance. Hmi1 is a helicase essential for the maintenance of the functional mitochondrial genome of S. cerevisiae. Unlike most helicases, ATP hydrolysis is partially dispensable for the Hmi1 function. The results of this thesis indicate, that Hmi1 has ATP hydrolysis dependent and independent function in the cell. Collectively, the results of this thesis show how diverse are the mitochondrial helicases and give an insight into the complex system of maintaining the mitochondrial DNA.
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