Project description
Uncovering a hidden player in cancer metabolism
Cancer cells need large amounts of energy and molecular building blocks to proliferate. Among these materials are purine nucleotides, molecules that serve as the building blocks of DNA and RNA. The enzyme NUDT5 has recently emerged as a key player in cellular metabolism, influencing purine production in unexpected ways. Beyond its catalytic role, NUDT5 may also act as a scaffold that organises protein complexes during nucleotide synthesis. With the support of the Marie Skłodowska-Curie Actions programme, the purine synthesis project will dissect the molecular mechanism of NUDT5 mode of action. In this context, researchers will employ proteomics, metabolomics, and structural biology. By revealing how NUDT5 regulates cancer metabolism, the project will pave the way for innovative treatments.
Objective
Proliferation of tumour cells requires continuous DNA synthesis and energy supply. Purine nucleotides are essential building blocks for DNA. Recent research has highlighted the role of NUDIX hydrolase 5 (NUDT5) catalytic activity in nuclear ATP metabolism in breast cancer. Notably, NUDT5 has also been suggested as a more general prognostic marker for various cancers, and NUDT5 depletion leads to suppression of tumour cell proliferation in a variety of model systems. Strikingly, the host lab has recently discovered that NUDT5 possesses an unexpected non-enzymatic, likely scaffolding role in de novo purine synthesis. This observation is unprecedented for a catalytically active member of the NUDIX family.
In this project, I aim to dissect the molecular mechanism and reveal the structural basis of NUDT5-regulated purine metabolism by combining Affinity Purification Mass Spectrometry (AP-MS) proteomics and metabolomics with X-ray crystallography and cryogenic Electron Microscopy (cryo-EM) with three main goals:
(1) Unravel the molecular mechanism and role of NUDT5 in purine synthesis using a comparative metabolomics and proteomics approach using CRISPR knock out (KO) cell lines, small molecule inhibitors and degraders of NUDT5 in relevant cell line models.
(2) Identify and define the NUDT5 interactome via AP-MS, and validate candidate NUDT5 interactors in biophysical and functional assays using purified proteins and cellular models.
(3) Explore NUDT5 protein complexes using X-ray crystallography and cryo-EM to dissect the molecular interaction between NUDT5 and complex partners for regulation of purine synthesis.
This work will offer novel fundamental insights into the molecular mechanism of NUDT5-mediated purine metabolism, and the scaffolding role of this enzyme to provide new perspectives on cellular metabolism and potential anti-tumour drug development.
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.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics DNA
- natural sciences earth and related environmental sciences geology mineralogy crystallography
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics nucleotides
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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Topic(s)
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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.
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.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2024-PF-01
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
OX1 2JD Oxford
United Kingdom
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