Project description
Delineating chromosomal architecture during mitosis
Eukaryotic cells temporally regulate DNA replication at multiple origins throughout chromosomes. Failure to do so results in genomic stress and may lead to cancer. The scope of the EU-funded COSMOS project is to understand the mechanism behind this temporal regulation and delineate the propagation of the structural elements at the chromosomal origins of replication during mitosis. To achieve this, researchers will employ Hi-C, a method for studying the three-dimensional architecture of genomes, to generate information separately for each sister chromatid. Insight into the interplay between replication timing, DNA damage and chromosome structure will help scientists comprehend the causes of chromosomal aberrations with obvious consequences for cancer therapy.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
CB2 1TN Cambridge
United Kingdom