Targeting mitochondrial DNA repair for novel anti-cancer therapies (Q84259)
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Project Q84259 in Poland
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | Targeting mitochondrial DNA repair for novel anti-cancer therapies |
Project Q84259 in Poland |
Statements
3,200,000.0 zloty
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3,200,000.0 zloty
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100.0 percent
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1 March 2018
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28 February 2023
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UNIWERSYTET GDAŃSKI
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Mitochondrial DNA, partially associated with mitochondrial inner membrane, is at the heart of ROS production thus, relative to nuDNA, mtDNA contains high levels of oxidative damage. Many of these damages are mutagenic and cause disease. Located on the inner membrane, base excision repair pathway is a major defense mechanism against oxidative damage. EXOG, a membrane-bound 5'-exo/endonuclease, is crucial for mtDNA repair. Depletion of EXOG causes accumulation of DNA damage in the mitochondria, but not in the nucleus, increases oxidative stress and mitochondrial dysfunction and leads to cell death. We propose that N-terminal transmembrane domain of EXOG anchors BER repairosome to mitochondrial inner membrane and modulates crucial 5'exonuclease activity of the enzyme. Because preservation of mtDNA integrity in cancer cells is a key for cancer progression, we aim to develop inhibitors to specifically halt function of EXOG and increase sensitivity to traditional chemotherapeutics. (Polish)
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Mitochondrial DNA, partially associated with mitochondrial inner membrane, is at the heart of ROS production thus, relative to boring, mtDNA contains high levels of oxidative damage. Many of these damages are Mutagenic and cause disease. Located on the inner membrane, base excision repair pathway is a major defense mechanism against oxidative damage. EXOG, a membrane-bound 5'-exo/endonuclease, is crucial for mtDNA repair. Depletion of EXOG causes accumulation of DNA damage in the mitochondria, but not in the nucleus, increases oxidative stress and mitochondrial dysfunction and leads to cell death. We propose that N-terminal transmembrane domain of EXOG anchors BER repairosome to mitochondrial inner membrane and modulates crucial 5'exonuclease activity of the enzyme. Because preservation of mtDNA integrity in cancer cells is a key for cancer progression, we aim to develop inhibitors to specifically halt function of EXOG and increase sensitivity to traditional chemotherapeutics. (English)
14 October 2020
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L’ADN mitochondrial, partiellement associé à la membrane interne mitochondriale, est au cœur de la production de ROS ainsi, par rapport à l’ADNmt ennuyeux, contient des niveaux élevés de dommages oxydatifs. Bon nombre de ces dommages sont mutagènes et causent des maladies. Situé sur la membrane interne, la voie de réparation de l’excision de base est un mécanisme de défense majeur contre les dommages oxydatifs. EXOG, un 5'-exo/endonucléase membranaire, est crucial pour la réparation de l’ADNmt. L’épuisement d’EXOG provoque une accumulation de dommages à l’ADN dans les mitochondries, mais pas dans le noyau, augmente le stress oxydatif et la dysfonction mitochondriale et entraîne la mort cellulaire. Nous proposons que le domaine transmembranaire N-terminal d’EXOG ancre le réparateur BER à la membrane interne mitochondriale et module l’activité cruciale de la 5’exonucléase de l’enzyme. Étant donné que la préservation de l’intégrité de l’ADNm dans les cellules cancéreuses est une clé de la progression du cancer, nous visons à développer des inhibiteurs afin d’arrêter spécifiquement la fonction d’EXOG et d’accroître la sensibilité à la chimiothérapie traditionnelle. (French)
30 November 2021
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Identifiers
POIR.04.04.00-00-3E44/17
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