CORDIS - Forschungsergebnisse der EU
CORDIS

The Conformation Of S-phase chroMOSomes

Projektbeschreibung

Darstellung der chromosomalen Architektur während der Mitose

Eukaryotische Zellen regulieren in allen Chromosomen die DNA-Replikation an verschiedenen Entstehungspunkten zeitlich. Treten dabei Fehler auf, kommt es zu genomischem Stress, was zu Krebs führen kann. Das EU-finanzierte Projekt COSMOS will die Mechanismen hinter dieser zeitlichen Regulation klären und die Verbreitung dieser strukturellen Elemente am chromosomalen Ursprung der Replikation während der Mitose darstellen. Dazu wird das Forschungsteam Hi-C nutzen, eine Methode zur Untersuchung der dreidimensionalen Architektur der Genome, um separate Informationen für jedes der Schwesterchromatide zu gewinnen. Durch Erkenntnisse zum Wechselspiel zwischen der Replikationszeit, DNA-Schäden und der Chromosomenstruktur wird die Wissenschaft die Ursachen von chromosomalen Aberrationen mit offensichtlichen Folgen für die Krebstherapie verstehen können.

Ziel

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.

Koordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Netto-EU-Beitrag
€ 271 732,80
Adresse
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
Vereinigtes Königreich

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Region
East of England East Anglia Cambridgeshire CC
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 271 732,80

Partner (1)