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MITOQUAD SIGNED

Unveiling the mitochondrial role of DNA2, a human helicase-nuclease causing mtDNA deletion associated syndrome.

Total Cost €

EC-Contrib. €

Partnership

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MITOQUAD project word cloud

Explore the words cloud of the MITOQUAD project. It provides you a very rough idea of what is the project "MITOQUAD" about.

dna protein genetic ophtalmoplegia variety biological human associates formed dna2 patients symptoms polymerase aging maintained neuromuscular disorders prevent hdna2 recruitment deletions mitochondria external metabolism replicative treat quadruplexes medical model question mtdna structure found recombinant disease accumulation gene peo progress gamma clarification employ mechanism alzheimer biochemical inducible elusive function elucidate parkinson pol vitro deeper replication integrity dissect inherited components helicase localizes machinery give mitoquad progressive vivo quadruplex reported remained multiple precise caused mutations of nuclease mutated interestingly twinkle mechanisms neurodegenerative occurrence cell mitochondrial disorder yeast stranded diseases

Project "MITOQUAD" data sheet

The following table provides information about the project.

Coordinator	UMEA UNIVERSITET Organization address address: UNIVERSITETOMRADET city: UMEA postcode: 901 87 website: www.umu.se contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
Coordinator Country	Sweden [SE]
Total cost	185˙857 €
EC max contribution	185˙857 € (100%)
Programme	1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
Code Call	H2020-MSCA-IF-2016
Funding Scheme	MSCA-IF-EF-ST
Starting year	2018
Duration (year-month-day)	from 2018-01-01 to 2019-12-31

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	UMEA UNIVERSITET UMEA UNIVERSITET Organization address address: UNIVERSITETOMRADET city: UMEA postcode: 901 87 website: www.umu.se contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	SE (UMEA)	coordinator	185˙857.00

Map

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.

Publications

List of publications.
year	authors and title	journal	last update
2020	Jan Jamroskovic, Mara Doimo, Karam Chand, Ikenna Obi, Rajendra Kumar, Kristoffer BrÃ¤nnstrÃ¶m, Mattias HedenstrÃ¶m, Rabindra Nath Das, Almaz Akhunzianov, Marco Deiana, Kazutoshi Kasho, Sebastian Sulis Sato, Parham L. Pourbozorgi, James E. Mason, Paolo Medini, Daniel Ã–hlund, Sjoerd Wanrooij, Erik Chorell, Nasim Sabouri Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization published pages: 2876-2888, ISSN: 0002-7863, DOI: 10.1021/jacs.9b11232	Journal of the American Chemical Society 142/6	2020-04-24
2018	Ali Al-Behadili, Jay P Uhler, Anna-Karin Berglund, Bradley Peter, Mara Doimo, Aurelio Reyes, Sjoerd Wanrooij, Massimo Zeviani, Maria Falkenberg A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL published pages: 9471-9483, ISSN: 0305-1048, DOI: 10.1093/nar/gky708	Nucleic Acids Research 46/18	2020-04-24

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