6533b85afe1ef96bd12b8c1f
RESEARCH PRODUCT
The Friedreich's Ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals
Gunnar DrewesMichael RistowMarkus FusserDoreen KuhlowRené ThierbachRené ThierbachPablo SteinbergPablo SteinbergTim J. SchulzHansruedi GlattUrte BlumeUrte BlumeBernd EpeAnja VoigtCarina Reichesubject
Iron-Sulfur ProteinsDNA Repairmedicine.disease_causeBiochemistryDNA Glycosylases8-oxoG 78-dihydro-8-oxoguanineMice0302 clinical medicineIron-Binding Proteinsoxidative stressBER base excision repairCells CulturedMammalsMice Knockout0303 health sciencesfrataxinDMEM Dulbecco's modified Eagle's mediumbiologyLiver NeoplasmsSalmonella entericairon–sulfur clusterLife SciencesIron-binding proteinsTransfection3. Good healthLB Luria–BertaniOGG1 8-oxoguanine DNA glycosylase 1ISC iron–sulfur clusterFpg formamido-pyrimidine DNA glycosylaseHPRT hypoxanthine phosphoribosyltransferaseResearch ArticleDNA damageDNA repairSSB DNA single-strand breakTransfectionCell Line03 medical and health sciencesFRDA Friedreich's ataxiaROS reactive oxygen speciesmedicineAnimalsHumansMUTYH human mutY homologue (Escherichia coli)Molecular BiologyGene030304 developmental biologyFriedreich's ataxiaCell BiologyFibroblastsMolecular biologytumorigenesisProkaryotic CellsFriedreich AtaxiaDNA base excision repairDNA glycosylaseMutationHepatocytesFrataxinbiology.proteinInstitut für ErnährungswissenschaftCarcinogenesisMAPK mitogen-activated protein kinase030217 neurology & neurosurgeryDNA Damagedescription
DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2010-10-25 |