BRCA INSIGHTS
Financiado
Understanding the functions of the BRCA protein complexes in DNA break repair an...
Understanding the functions of the BRCA protein complexes in DNA break repair and in replication stress
BRCA1, BRCA2 and associated factors are frequently mutated in familial and sporadic cancers of the breast and ovary. The BRCA proteins have canonical functions together with the RAD51 recombinase in DNA double-strand break repair...
BRCA1, BRCA2 and associated factors are frequently mutated in familial and sporadic cancers of the breast and ovary. The BRCA proteins have canonical functions together with the RAD51 recombinase in DNA double-strand break repair by homologous recombination. More recently, it was discovered that the same proteins have separate, recombination-independent roles in the metabolism of challenged replication forks. It is currently debated whether defects in the canonical and/or non-canonical functions of BRCA contribute to tumorigenesis.
As BRCA1 and BRCA2 function in various processes, interact with numbers of co-factors, and can be extensively post-translationally modified, phenotypes associated with their defects are often very pleiotropic. Here I propose to use a biochemical approach, which will allow us to study the precise functions of these proteins with defined substrates and co-factors in controlled systems. BRCA1 and BRCA2 represent some of the largest factors in human proteome. Using state-of-the-art protein expression strategies, we are now able to produce sufficient quantities of the respective complexes in their native or post-translationally modified states to make biochemistry feasible.
We aim to define how the BRCA proteins help couple the initial steps in DNA break repair including nucleolytic processing of DNA breaks, RAD51 loading on ssDNA and subsequent invasion of homologous DNA template. We will also determine the precise non-canonical functions of RAD51, RAD52 and BRCA1/2 complexes in fork remodeling, fork protection and fork restart, which prevents pathological degradation of nascent DNA under replication stress. We anticipate that these diverse functions of BRCA proteins are governed by their co-factors, post-translational modifications and specific substrates. A biochemical approach is uniquely suited to understand the mechanisms how BRCA proteins regulate DNA metabolic pathways to promote genome stability and prevent tumorigenesis.
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Duración del proyecto: 69 meses
Fecha Inicio: 2021-06-03
Fecha Fin: 2027-03-31
Fecha Fin: 2027-03-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2021-06-03
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2020-ADG:
ERC ADVANCED GRANT
Cerrada
hace 4 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
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FONDAZIONE PER LISTITUTO DI RICERCA IN BIOMED...
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Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
245.22K€ |
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