Nucleotide metabolism and cancer: structure and function of the thymidylate synthesis complex
| Componente | Categoria |
|---|---|
| Lucia Marcocci | Componenti strutturati del gruppo di ricerca |
| Laura Cervoni | Componenti strutturati del gruppo di ricerca |
| Alessio Paone | Componenti strutturati del gruppo di ricerca |
| Componente | Qualifica | Struttura | Categoria |
|---|---|---|---|
| Maria Chiara Magnifico | assegnista CNR | CNR | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca |
| Giovanna Boumis | Tecnico | Dip. Scienze Biochimiche/Sapienza Università di Roma | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca |
| Adele Di Matteo | Ricercatore CNR | CNR | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca |
A universal trait of cancer cells is uncontrolled growth, requiring an extra input of energy and metabolite precursors to support proliferation. Serine, Glycine One Carbon metabolism (OCM) plays a pivotal role in cancer development, providing cells with the building blocks, including nucleotide precursors and reducing power, necessary to maintain high rates of proliferation.
When cells proliferate, increased nucleotide synthesis is necessary for DNA replication.
A key role in these processes is played by folate-dependent de novo dTMP synthesis complex (dTMP-SC), which involves the enzymes serine hydroxymethyltransferase (SHMT), dihydrofolate reductase (DHFR), and thymidylate synthase (TYMS). SHMT1 is a critical part of dTMP-SC and changes in SHMT1 expression directly impact de novo dTMP synthesis by affecting dTMP-SC assembly and its inactivation causes uracil misincorporation.
The aim of this project is to understand how the dTMP synthesis complex is assembled and functions, in order to provide the basis for its selective targeting in cancer.
In particular, we plan to:
-Elucidate the structure of the dTMP synthesis complex and the role of SHMT1 within the complex. We will study the protein/protein interactions in the dTMP-SC by means of site-directed mutagenesis and various biophysical techniques such as calorimetry, fluorescence spectroscopy, biocrystallography and cryo-Electron Microscopy.
-Investigate the molecular bases of SHMT interactions with nucleic acids and their relevance in different cellular compartments, by means of biophysical techniques, and also molecular and cell biology approaches.
The results of this study will allow us to advance the molecular understanding of the dTMP synthesis complex, a challenging goal which will provide the conceptual framework to design alternative therapeutic approaches to target cell proliferation in cancer.