MITOQUAD · Unveiling the mitochondrial role of DNA2, a human helicase-nuclease causing mtDNA deletion associated syndrome.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-01-01 → 2019-12-31
- EU contribution
- €185,857
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Unveiling the mitochondrial role of DNA2, a human helicase-nuclease causing mtDNA deletion associated syndrome.
Mitochondria are key organelles as they are responsible for supplying the proper form of energy necessary to the cell to exert all its functions. Conversely to other cellular compartments, they possess their own DNA (mtDNA). The genes encoded by this small genome are essential for the function of the mitochondria. Multiple deletions in mtDNA give rise to a variety of neuromuscular symptoms, associated with genetic inherited disorders and aging. Moreover, mtDNA deletions have been reported in patients with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. In spite of its medical importance, not much is yet known about the mechanisms by which mtDNA deletions are formed. Recently, in silico and in vitro analyses reveal that mtDNA deletion breakpoints occur preferentially at specific secondary DNA structures called G-quadruplexes (GQs). GQs are nucleic acid sequences rich in guanines that can assemble into a four-strand structures. mtDNA is enriched in sequences with the potential to form GQs, but their occurrence in vivo, as well as their function and implication on mtDNA replication, are still under debate. In the nuclear DNA (nDNA), GQs are involved in the regulation of different biological processes such as replication, transcription and telomere maintenance and their dynamic is modulated by several proteins. Among them, the nuclease-helicase DNA2 has been shown to resolve GQs occurring in the nDNA. Human DNA2 localizes also in the mitochondria but its role in this organelle is still elusive. Notably, DNA2 was reported to be mutated in patients with autosomal-dominant progressive external ophthalmoplegia (adPEO), a condition characterized by the accumulation of multiple deletions in mtDNA. The main goal of this project is to investigate the dynamic of G-quadruplexes formation in the mtDNA and the role of DNA2 in their resolution. This is a relevant question to understand whether GQs account for mtDNA deletions formation and accumulation in vivo.
Data: CORDIS, © European Union
Project objective
Multiple deletions in mtDNA give rise to a variety of neuromuscular symptoms, often associated with genetic inherited disorders and aging and they have been reported in patients with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. In spite of its medical importance, not much is yet known about the mechanisms by which mtDNA deletions are formed. Progressive external ophtalmoplegia (PEO) is one of the conditions characterized by the accumulation of mtDNA deletions. This disease is caused by mutations in components of the mtDNA replication machinery, like the DNA polymerase γ (POLγ) and the replicative helicase TWINKLE. Recently, also the helicase-nuclease DNA2 has been found mutated in patients affected by this disorder. The precise function of human DNA2 (hDNA2) has remained elusive. hDNA2 localizes to mitochondria and has the biochemical properties to process four-stranded DNA structure (G-quadruplexes). Interestingly, G-quadruplex DNA associates with mtDNA deletions formation in human diseases. To dissect the mitochondrial role of hDNA2, I will focus on the mechanism of hDNA2 recruitment to mtDNA. Then I will address the role of DNA2 in mitochondria metabolism and in G-quadruplexes mtDNA metabolism and I will characterize the consequences of disease-associated mutations in DNA2 gene. I will employ a range of in vitro (based on recombinant protein) and in vivo (inducible cell systems and yeast model).The clarification of the hDNA2 mitochondrial biological function will help to elucidate the mechanism by which mtDNA deletions are formed in mitochondrial disorders. Moreover, MITOQUAD project will lead to a deeper understanding of how mtDNA integrity is maintained, a relevant question for understanding the early development and progress of a large number of mitochondrial disorders, in order to treat or prevent their occurrence.
Original text from CORDIS.
Participants
- UMEA UNIVERSITET · UMEACoordinatorSweden
Links
Data: CORDIS, © European Union