Signalisation moléculaire par le système de réparation des mésappariements de l'ADN et l'agent anticancéreux cisplatine : étude des interactions protéine MutS-composé de lésion du cisplatine

Abstract : The DNA mismatch repair (MMR) system participates in the cytotoxicity of the anticancer agent cisplatin by triggering an apoptotic pathway and a deficiency is associated in vivo with cisplatin resistance in cancer cells. To determine at the molecular level how MMR proteins can signal cisplatin DNA damage, we have studied the interaction of the MutS bacterial protein and a cisplatin compound lesion (i.e. a d(GpG) cisplatin intrastrand cross-link on one strand and a mismatched base opposite one of the platinated guanines). My work was mainly devoted to i) a study of biochemical ATP-dependent properties of MutS in the presence of DNA containing a unique cisplatin compound lesion ii) an interaction study of a set of cisplatin compound lesions with the HMGB1 rat protein that is well known as being capable to inhibit repair proteins accessibility to cisplatin lesions. Our study was performed by techniques from molecular biology, biochemistry and spectroscopy (surface plasmon resonance). We showed that a cisplatin compound lesion modulates several ATP-dependent properties of MutS, one unexpected property being the inhibition of MutS release from DNA. Our data suggest that a cisplatin compound lesions can participate to MMR-dependent signalling by modulation of repair initiation steps and are in agreement with the model of “MMR-dependent direct signalling”.
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Submitted on : Monday, May 25, 2009 - 3:03:30 PM
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  • HAL Id : tel-00387491, version 1

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Yuliya Sedletska. Signalisation moléculaire par le système de réparation des mésappariements de l'ADN et l'agent anticancéreux cisplatine : étude des interactions protéine MutS-composé de lésion du cisplatine. domain_other. Université d'Orléans, 2007. Français. ⟨tel-00387491⟩

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