Regulation of pol-eta by phosphorylation, ubiquitination and SUMOylation

Projektinformationen

TLSCHECK

ID Finanzhilfevereinbarung: 303806

Projekt abgeschlossen

Startdatum 1 März 2012

Enddatum 29 Februar 2016

Finanziert unter

• Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Gesamtkosten € 100 000,00

EU-Beitrag € 100 000,00

Koordiniert durch

CONSIGLIO NAZIONALE DELLE RICERCHE
Italy

Ziel

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.

Wissenschaftliches Gebiet

• medical and health sciences › clinical medicine › oncology › skin cancer
• natural sciences › biological sciences › genetics › DNA
• natural sciences › biological sciences › genetics › mutation

Programm/Programme

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Thema/Themen

• FP7-PEOPLE-2011-CIG - Marie-Curie Action: "Career Integration Grants"

Aufforderung zur Vorschlagseinreichung

FP7-PEOPLE-2011-CIG
Andere Projekte für diesen Aufruf anzeigen

Finanzierungsplan

MC-CIG - Support for training and career development of researcher (CIG)

Koordinator

CONSIGLIO NAZIONALE DELLE RICERCHE

Kontakt Verwaltung

Stefano Lussignoli (Dr.)

• EU-Beitrag: € 100 000,00
• Adresse: PIAZZALE ALDO MORO 7 ; 00185 Roma ; Italien
• Region: Centro (IT) › Lazio › Roma
• Aktivitätstyp: Research Organisations
• Gesamtkosten: Keine Daten