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|ROLE OF HR -AND NHES- DEFICIENCY ON IN VIVO ABSCORAL ONCOGENIC RESPONSE
|Ruolo dell’assenza dei meccanismi di riparazione delle DSBs (HR e NHEJ) nella risposta oncogenica abscopale
DOUBLE STAND BREAK RADIATION
|Università degli studi Roma Tre
|Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. Ionizing radiation (IR) is a genotoxic agent and human carcinogen. DNA double-strand breaks (DSBs) are considered the most biologically damaging lesions produced by IR and were detected both in directly-exposed and shielded tissues, demonstrating that an incorrect repair of the damage may be responsible for the onset of tumors. Here, we investigate the role of DNA DSBs-repair systems - Homologous Recombination (HR) and Non-Homologous End-Joining (NHEJ)- in the resolution of the abscopal DNA damage induced by IR, in mouse central nervous system using double knockout mouse models in which HR or NHEJ are downregulated (Ptch1+/−/Rad54-/- , Ptch1+/−/DNA-PKcs-/- , Ptch1+/− /DNA-PKcs+/-). We show the involvement of NHEJ pathway in the resolution of abscopal DNA damage and tumor induction in non-targeted cerebellum, providing unequivocal evidence for the role of functional DNA-PKcs in the expression of oncogenic damage in tissues remote from the irradiated field. This data are verified and confirm using a pharmacological treatment strategy. TPO is the molecule of interest, capable of modulating the DNA repair pathway. TPO modulates the efficiency of the NHEJ pathway suggesting that DNA repair activity is a specific function of TPO. Our data provide a novel hypothesis for use new drugs aimed at modulating DNA DSB repair activity and highlight recent advances in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy especially in the protection of unexposed tissues after partial-body irradiation relevant in the radiotherapy context.
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|Dipartimento di Scienze
T - Tesi di dottorato
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checked on Feb 24, 2024
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