Descripción del proyecto
Delineación de la estructura cromosómica durante la mitosis
Las células eucariotas regulan temporalmente la replicación del ADN en múltiples orígenes a través de los cromosomas. En caso contrario, se produce estrés genómico y puede desarrollarse cáncer. El proyecto financiado con fondos europeos COSMOS tiene por objetivo comprender el mecanismo subyacente a esta regulación temporal y delinear la propagación de elementos estructurales en los orígenes cromosómicos de replicación durante la mitosis. Para ello, los investigadores emplearán Hi-C, un método para estudiar la estructura tridimensional de los genomas y obtener información de forma independiente para cada cromátida hermana. La información sobre la interrelación entre el momento de la replicación, los daños del ADN y la estructura cromosómica ayudará a los científicos a comprender las causas de las anomalías cromosómicas, con las consiguientes consecuencias obvias para los tratamientos oncológicos.
Objetivo
DNA replication initiation is strictly regulated to ensure complete genome duplication. In eukaryotes, temporal control of origin firing across chromosomes establishes replication timing domains. Failures in the timing of replication initiation across chromosomes is implicated in DNA replication stress, a hallmark of cancer, but the function of these temporally restricted replication domains is not understood. As well as the duplication of DNA, S-phase involves the duplication of all chromosome structural elements and the complete separation of chromosomal intertwines. How this is achieved is poorly understood.
A major hurdle for understanding how 3D chromosomal structures are duplicated in S-phase and inherited through mitosis is that current Hi-C methodologies do not give a distinction between chromatids during or immediately after DNA replication. This project aims to visualise the structure and interactions of replicating chromosomes by developing a new Hi-C method which will allow a separate analysis of each new sister chromatid during its formation. This will provide unique information about how DNA loops and interactions are replicated and resolved, preventing the accumulation of toxic chromosomal defects in each new daughter. This method will then be extended to address the impact of replication stress for the inheritance of chromosome structure. The project will result in a new understanding of the interplay of replication timing, DNA damage and chromosome structure, which may provide a novel framework to understand the causes of chromosomal aberrations that accompany tumour progression.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
CB2 1TN Cambridge
Reino Unido