The transcription-coupled DNA repair-initiating protein CSB promotes XRCC1 recruitment to oxidative DNA damage

Transcription-coupled nucleotide excision repair factor Cockayne syndrome protein B (CSB) was suggested to function in the repair of oxidative DNA damage. However thus far, no clear role for CSB in base excision repair (BER), the dedicated pathway to remove abundant oxidative DNA damage, could be established. Using live cell imaging with a laser-assisted procedure to locally induce 8-oxo-7,8-dihydroguanine (8-oxoG) lesions, we previously showed that CSB is recruited to these lesions in a transcription-dependent but NER-independent fashion. Here we showed that recruitment of the preferred 8-oxoG-glycosylase 1 (OGG1) is independent of CSB or active transcription. In contrast, recruitment of the BER-scaffolding protein, X-ray repair cross-complementing protein 1 (XRCC1), to 8-oxoG lesions is stimulated by CSB and transcription. Remarkably, recruitment of XRCC1 to BER-unrelated single strand breaks (SSBs) does not require CSB or transcription. Together, our results suggest a specific transcription-dependent role for CSB in recruiting XRCC1 to BER-generated SSBs, whereas XRCC1 recruitment to SSBs generated independently of BER relies predominantly on PARP activation. Based on our results, we propose a model in which CSB plays a role in facilitating BER progression at transcribed genes, probably to allow XRCC1 recruitment to BER-intermediates masked by RNA polymerase II complexes stalled at these intermediates

BER: (Base excision repair): molecular mechanisms and biological roles

International audienceLa majorité des lésions de l'ADN résulte des réactions cellulaires endogènes : c'est le concept « d'ennemi de l'intérieur ». La voie de réparation par excision de bases (BER) est critique dans la lutte contre ces lésions. La BER implique l'action successive et coordonnée de quatre enzymes dont une ADN glycosylase qui doit reconnaître et extraire de l'ADN une base modifiée parmi des milliers de bases intactes. La BER contribue à la stabilité du génome et retarde le processus de cancérogenèse, et aussi à la variabilité des gènes des immunoglobulines

Oxidation status of human OGG1-S326C polymorphic variant determines cellular DNA repair capacity

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8-oxoguanine DNA glycosylase, but not Kin17 protein, is translocated and differentially regulated by estrogens in rat brain cells

8-oxoguanine DNA glycosylase and Kin17 are proteins widely distributed and phylogenetically conserved in the CNS. 8-oxoguanine DNA glycosylase is a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine present in DNA damaged by oxidative stress. Kin17 protein is involved in DNA repair and illegitimate recombination in eukaryotic cells. The present study evaluates the effect of ovarian hormones on the expression of both proteins in the magnocellular paraventricular nucleus of the hypothalamus and the bed nucleus of the stria terminalis in female and male rat brains. In the paraventricular nucleus, ovariectomy induced a significant decrease in the number of 8-oxoguanine DNA glycosylase-positive nuclei as well as in their relative fluorescent intensity as compared with ovariectomized-estradiol treated and proestrous groups. Confocal microscopy observation demonstrated that oxoguanine DNA glycosylase protein is located in the Hoechst-dyed nuclei and cytoplasm in male and ovariectomized rats. Surprisingly, following estradiol administration to ovariectomized and proestrous rats, the 8-oxoguanine DNA glycosylase immunolabeling was observed in the nucleolus, the cytoplasm and the dendrites of cells, while Kin17 protein was always localized in the cell nuclei. In the bed nucleus of the stria terminalis, the number of 8-oxoguanine DNA glycosylase-positive nuclei during proestrous was significantly lower than the number obtained in males and ovariectomized rats and similar to the number of ovariectomized-estradiol-treated groups. In contrast to these observations, no significant differences were observed in the expression of kin17 protein. Our results suggest that estrogens differentially regulate the expression of 8-oxoguanine DNA glycosylase, but not that of Kin17 protein, in specific regions of the rat brain and that estradiol can translocate the 8-oxoguanine DNA glycosylase protein within nuclei and to other subcellular compartment

APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process

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