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Dissecting the mechanism of DNA repair in human mitochondria

Project description

Mitochondrial DNA repair in eukaryotic cells

Mitochondrial DNA are located in eukaryotic cells in organelles mitochondria that convert chemical energy from food into a cellular form of energy like adenosine triphosphate. This DNA represents a small fraction of all cell DNA (human mitochondrial DNA includes 16 569 base pairs) and just as nucleus DNA has to be faithfully replicated. The process of mitochondrial oxydative phosphorylation produces reactive oxygen that could be damaging for DNA anchored to the inner mitochondrial membrane. It explains that this DNA has an additional unique repair mechanism not present in the nucleus and is enabled by multiple copies of mitochondrial DNA. Base excision repair pathway is a major protective mechanism against oxidative damage and is carried out by enzyme complexes termed mitochondrial repairosome, which mechanism of function is poorly understood. The goal of the EU-funded MitoRepairosome project is to provide insights into spatial assembly and molecular mechanics of human mitochondrial repairosome.

Objective

In mammalian cells genetic information is stored in two compartments: in the nucleus and in the mitochondria. DNA in mitochondria (mtDNA), just like in theIn mammalian cells genetic information is stored in two locations: in the nucleus and in mitochondria. DNA in mitochondria, just like in the nucleus, must be faithfully copied and mistakes (i.e. mutations due to exogenous and endogenous DNA damaging agents) lead to formation of DNA lesions. Persistence of these DNA lesions leads to genomic instability and human diseases like cardiovascular, skeletal muscular and neurological disorders, cancer as well as normal aging process. Mitochondrial DNA (mtDNA) is anchored to the inner mitochondrial membrane thus is in a close proximity to the electron transport chain and is subjected to a constant attack by reactive oxygen species (ROS), generated as byproducts of oxidative phosphorylation (OXPHOS). As a result mitochondria must have a robust DNA repair mechanism which becomes particularly important in non-dividing cells. It is accepted that DNA base excision repair (BER) pathway is a major defense mechanism against oxidative damage in human mitochondria. Aptly localized on mitochondrial inner membrane, mitochondrial BER enzymes: catalytic subunit of DNA polymerase (PolA) along with its accessory subunit, DNA polymerase (PolB), inner-membrane 5'-exo/endonuclease (EXOG), Apurinic/apyrimidinic endonuclease 1 (APE1) and Ligase 3 (Lig3) form a membrane-bound, high molecular weight, complexes called mitochondrial repairosome, capable of carrying out complete DNA repair. Although BER can be readily detected in mitochondria and major components have been identified, the spatial-temporal organization of mitochondrial repairosome and molecular mechanism by which mtDNA is repaired is not well understood. The goal of this research project is to provide fundamental mechanistic insights into the assembly, composition, activities and structures of human mitochondrial repairosome.

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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ERC-STG - Starting Grant

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Call for proposal

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(opens in new window) ERC-2019-STG

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Host institution

UNIWERSYTET GDANSKI
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 500 000,00
Address
UL JANA BAZYNSKIEGO 8
80-309 GDANSK
Poland

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Region
Makroregion północny Pomorskie Trójmiejski
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 500 000,00

Beneficiaries (1)

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