Year: 2018
Type: dissertation
Abstract: Mitochondria are tiny organelles inside most eukaryotic cells.They provide the energy for the cells to function and therefore are essential especially in highly metabolic tissues such as the heart or brain.Mitochondria contain their own DNA, the mitochondrial DNA (mtDNA), which must be replicated to be distributed between daughter cells or respond to rising energy demands.Moreover, mitochondria are thought to harbor an oxidative environment as a trade-off for their energy production.Damage on the mtDNA can impair replication and cause replication stalling, which can in turn lead to mtDNA genomic instability and mitochondrial diseases.These diseases are relatively common forms of neuromuscular disorders, affecting between 1:7,000 and 1:20,000 individuals under 16 years of age.Although extremely relevant, the diagnosis, prognosis and treatment of mitochondrial diseases are challenging due to their clinical and genetic heterogeneity.In spite of the important role that mtDNA plays in these disorders, little is known about its maintenance.For example, at least three different models of mtDNA replication have been proposed, including asynchronous, strand-coupled and recombination-mediated replication, and almost nothing is known about how mtDNA replication deals with a damaged DNA template (i.e., replication stress).This study investigates how mammalian mtDNA is replicated under different conditions and how mtDNA replication copes with replication stress.To address these questions, I used several animal cell lines which were exposed to different DNA-damaging agents, including UV light, KBrO3 (an inducer of oxidative damage) and dideoxycytidine (ddC, a specific inhibitor of mtDNA replication).These agents are expected to cause lesions on the mtDNA template or directly block replication, inducing artificial replication fork stalling and replication stress.If stalled forks are not rescued, they can finally collapse, inducing double-strand breaks and prompting mtDNA genetic instability.In prokaryotes and the eukaryotic nucleus, several options exist to rescue stalled forks, including recombination, fork regression and jamas habría sido capaz de acabar la carrera; y aún más importante, empezar un doctorado en otro país.A vosotros, mis padres, os debo en gran medida mi devoción por la ciencia.Aunque al final me decanté por los seres vivos más que por las rocas, vosotros me inculcásteis el afán por querer saber más; tanto a través de los libros, como disfrutando de la naturaleza.Gracias por alimentar mi curiosidad.Marcos, tu te mereces unas líneas a parte por todo el trabajo de edición de los gráficos y figuras que elegantemente ilustran esta tesis.Y junto a Noe, gracias por esa visita que me hicísteis.Cuando crezca un poco más el pequeñajo le podréis leer esta tésis para que se duerma.
Author: Torregrosa Muñumer, Ruben
Institution: University of Eastern Finland
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7014956689