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The Conformation Of S-phase chroMOSomes

Descrizione del progetto

Delineare l’architettura cromosomica durante la mitosi

Le cellule eucariote regolano a livello temporale la replicazione del DNA in diverse origini nei cromosomi. Il loro fallimento dà luogo a stress genomico e può condurre al cancro. L’obiettivo del progetto COSMOS, finanziato dall’UE, consiste nel comprendere il meccanismo alla base della regolazione temporale e delineare la propagazione degli elementi strutturali all’origine cromosomica della replicazione durante la mitosi. A tal fine, i ricercatori impiegheranno l’Hi-C, un metodo per studiare l’architettura tridimensionale dei genomi, al fine di generare separatamente informazioni per ogni cromatidio fratello. Le informazioni sull’interazione tra tempo di replicazione, danni al DNA e struttura del cromosoma aiuteranno gli scienziati a comprendere le cause delle aberrazioni cromosomiche, con ovvie conseguenze per la terapia tumorale.

Obiettivo

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.

Coordinatore

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Contribution nette de l'UE
€ 271 732,80
Indirizzo
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
Regno Unito

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Regione
East of England East Anglia Cambridgeshire CC
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 271 732,80

Partner (1)