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BRCA2Interact

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Structural and biochemical characterization of pre recombination complexes

Homologous recombination (HR) is an essential DNA repair mechanism and defects in different HR factors are linked with disease and cancer pre-disposition. The RAD51 recombinase plays a central role in HR, forming nucleoprotein fil... ver más

31/05/2017

The Francis Crick...

183K€

Presupuesto del proyecto: 183K€

Líder del proyecto

THE FRANCIS CRICK INSTITUTE LIMITED No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

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Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2017-05-31

MSCA-IF-2014-EF: Marie Skłodowska-Curie Individual F...

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2 Participantes

The Francis Crick Institute

183.45K€ | Lider

CR-UK

N.D. | Participante

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Duración del proyecto: 26 meses Fecha Inicio: 2015-03-17
Fecha Fin: 2017-05-31

Líder del proyecto

THE FRANCIS CRICK INSTITUTE LIMITED No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 183K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Homologous recombination (HR) is an essential DNA repair mechanism and defects in different HR factors are linked with disease and cancer pre-disposition. The RAD51 recombinase plays a central role in HR, forming nucleoprotein filaments at sites of DNA damage and promoting homologous pairing and DNA strand exchange. RAD51 filament formation is mediated by the BRCA2 tumour suppressor, mutations in which lead to a high incidence of developing breast cancer. BRCA2 interacts with other HR factors, such as PALB2 and members of the RAD51 paralog family. Many of these proteins also function as tumour suppressors. The host laboratory has purified full-length BRCA2 protein and shown that it facilitates RAD51-mediated HR by acting as a molecular chaperone for RAD51 filament formation. This offers a unique position to extend our understanding of pre-recombinational protein assembly by inclusion of additional critical HR factors, and answer the important question how PALB2 and the RAD51 paralogs coordinate their activities with BRCA2 to promote the assembly of RAD51 filaments. To achieve this, I propose to: i) Characterize the biochemical and structural properties of RAD51 paralog complexes ii) Define the interplay between BRCA2, PALB2, and the RAD51 paralogs in forming pre-recombination complexes for RAD51 assembly, using biochemical approaches and electron microscopic visualisation. Given the importance of HR and its role in tumour avoidance, I anticipate our results to provide significant new insights into the molecular mechanisms underlying genome instability. Also, they may uncover novel targets for therapeutic intervention for breast cancer. Together, the proposed research will not only substantially advance knowledge of DNA repair but will also provide me with invaluable training in biochemistry, electron microscopy and project management in a world-class research environment. As such, it forms the perfect platform from which to launch my independent research career.

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