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Regulating recombination in mitotic and meiotic cells

Obiettivo

DNA is a highly reactive molecule that is subject to deliberate, spontaneous and environmental damage. One of the most catastrophic lesions in DNA is the double-strand break (DSB), which if left unrepaired can result in cell death, infertility, genome instability and cancer. Homologous recombination (HR) is a largely error-free mechanism of DSB repair that utilizes an intact sister or homologous chromosome as a repair template. Despite considerable progress in understanding the mechanisms of HR, very little is known about how this process is regulated. My lab has made a number of seminal discoveries that have improved our understanding of how HR is regulated in mitotic and meiotic cells. In this ERC proposal, we plan to elucidate the mechanisms that control HR events in mitotic cells and regulate HR pathway choice during meiotic recombination. We will place particular emphasis on defining the roles of RTEL1 and HELQ1 in regulating HR in mitotic and meiotic cells and will determine how dysfunction of these genes contributes to tumorigenesis. Biochemistry and proteomic approaches will be employed to determine how the Fanconi anemia (FA) pathway counteracts error-prone repair by non-homologous end joining (NHEJ), thus favouring HR repair in S-phase. The use of NHEJ inhibitors as a potential treatment of FA will be tested in existing mouse models of FA. Finally, genetic screens and proteomic analysis of HR regulators will be performed in C. elegans to elucidate the mechanisms that regulate the choice between crossover and non-crossover pathways during meiotic HR. Thus, in the work proposed here, my lab will make use of multiple experimental approaches to elucidate the mechanisms for control of HR and the consequences of dysregulated HR on human disease.

Invito a presentare proposte

ERC-2010-AdG_20100317
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Meccanismo di finanziamento

ERC-AG - ERC Advanced Grant
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Coordinatore

THE FRANCIS CRICK INSTITUTE LIMITED
Indirizzo
1 midland road
NW1 1AT London
Regno Unito

Mostra sulla mappa

Regione
London Inner London — West Camden and City of London
Tipo di attività
Research Organisations
Contatto amministrativo
Stéphane Maikovsky (Mr.)
Ricercatore principale
Simon Joseph Boulton (Dr.)
Collegamenti
Contributo UE
Nessun dato

Beneficiari (2)