title: Rapid inactivation and proteasome-mediated degradation of OGG1 contribute to the synergistic effect of hyperthermia on genotoxic treatments.
abstract: Inhibition of DNA repair has been proposed as a mechanism underlying heat-induced sensitization of tumour cells to some anticancer treatments. Base excision repair (BER) constitutes the main pathway for the repair of DNA lesions induced by oxidizing or alkylating agents. Here, we report that mild hyperthermia, without toxic consequences per se, affects cellular DNA glycosylase activities, thus impairing BER. Exposure of cells to mild hyperthermia leads to a rapid and selective inactivation of OGG1 (8-oxoguanine DNA glycosylase) associated with the relocalisation of the protein into a detergent-resistant cellular fraction. Following its inactivation, OGG1 is ubiquitinated and directed to proteasome-mediated degradation, through a CHIP (C-terminus of HSC70-interacting protein) E3 ligase-mediated process. Moreover, the residual OGG1 accumulates in the perinuclear region leading to further depletion from the nucleus. As a consequence, HeLa cells subjected to hyperthermia and exposed to a genotoxic treatment have a reduced capacity to repair OGG1 cognate base lesions and an enhanced cell growth defect. The partial alleviation of this response by OGG1 overexpression indicates that heat-induced glycosylase inactivation contributes to the synergistic effect of hyperthermia on genotoxic treatments. Taken together, our results suggest that OGG1 inhibition contributes to heat-induced chemosensitisation of cells and could lay the basis for new anticancer therapeutic protocols that include hyperthermia.
authors: CEA, Institute of Molecular and Cellular Radiobiology, 18 route du Panorama, Fontenay aux Roses, F-92265, France.
authors: Damiano
authors: D
authors: Fantini
authors: Eva
authors: E
authors: Moritz
authors: Frédéric
authors: F
authors: Auvré
authors: Rachel
authors: R
authors: Amouroux
authors: Anna
authors: A
authors: Campalans
authors: Bernd
authors: B
authors: Epe
authors: Anne
authors: A
authors: Bravard
authors: J Pablo
authors: JP
authors: Radicella
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004795:Enzyme Stability; D006367:HeLa Cells; D018869:Heat-Shock Response; D006801:Humans; D017319:Photosensitizing Agents / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D021381:Protein Transport; D059748:Proteolysis; D011759:Pyrrolidines / Q000494:pharmacology; D011807:Quinolizines / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D017319:Photosensitizing Agents; D011759:Pyrrolidines; D011807:Quinolizines; C076809:Ro 19-8022; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D046988:Proteasome Endopeptidase Complex