Objectif Xeroderma pigmentosum variant (XPV) is an autosomal recessive genetic disorder that results in enhancced predisposition to skin cancers. XPV results from a defect in the translesion synthesis (TLS) polymerase poleta. TLS allows bypass of unrepaired damage permitting completion of replication. Poleta is phosphorylated and ubiquitinated and can interact with ubiquitin and SUMO, two post-translational modifications that are important in a number of DNA repair pathways, via multiple domains. Mutants in those domains show a defect in DNA damage checkpoint activation, pointing out an unexpected connection between TLS and one of the DNA damage surveillance mechanisms. TLS is regulated by ubiquitination of the proliferating cell nuclear antigen (PCNA). While PCNA ubiquitination is essential for TLS, new evidence suggests that is not needed for the initial recruitment of the polymerases to chromatin. The objective of this proposal is to identify how poleta’s function is modulated by interaction of a number of unknown factors with its different domains, ensuring both its recruitment when needed and its inhibition when its action would be deleterious for normal replication. I propose to dissect the checkpoint activation cascade to unveil the role of poleta in this pathway, analyze known factors involved in both the ubiquitination and SUMOylation pathways and to conduct a proteomic study of poleta to identify novel interactors which will be assayed for TLS functionality in vivo. Insight into the function of a core cancer protection pathway, plus the potential identification of new and important partners controlling poleta will lead to finding new diagnostically relevant biomarkers for XPV patients in whom mutations in poleta have not been found. In the long-term, Y-family polymerases are likely candidate targets for synthetic lethality strategies in cancer treatment and thus a mechanistic understanding of their function will be essential to designing rational therapies. Champ scientifique medical and health sciencesclinical medicineoncologyskin cancernatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsmutation Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2011-CIG - Marie-Curie Action: "Career Integration Grants" Appel à propositions FP7-PEOPLE-2011-CIG Voir d’autres projets de cet appel Régime de financement MC-CIG - Support for training and career development of researcher (CIG) Coordinateur CONSIGLIO NAZIONALE DELLE RICERCHE Contribution de l’UE € 100 000,00 Adresse PIAZZALE ALDO MORO 7 00185 Roma Italie Voir sur la carte Région Centro (IT) Lazio Roma Type d’activité Research Organisations Contact administratif Stefano Lussignoli (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
