Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine oncology skin cancer
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences genetics mutation
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2011-CIG
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MC-CIG - Support for training and career development of researcher (CIG)
Coordinator
00185 Roma
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.