Cellular response to DNA replication stress

Complete, accurate genome replication is essential for all life on earth. However, the machines that replicate the DNA must overcome many obstacles, including transcription and DNA damage, collectively termed ‘replication stress’.

A replication fork that encounters an obstacle may stall and activate a cellular surveillance mechanism, called a checkpoint. The activated checkpoint stabilises the stalled replication fork and inhibits further DNA replication to prevent the accumulation of further problems. This project will apply our cutting-edge single molecule, genomic technology to discover how cells respond to replication stress.

We offer a highly collaborative, multi-disciplinary PhD between the Nieduszynski (DNA replication; technology development) and Blow (cell cycle control; cell biology; biochemistry) groups. The main aim of the project is to discover the mechanism by which excess Mcm2-7 protein loading ensures complete genome replication in the presence and absence of replication stress.

You The student will work in a rapidly developing field and gain a unique expertise in nanopore single molecule sequencing, technology development and computational biology – skills that are in high demand for modern biological research in both academia and industry.

The project will be conducted at the Earlham Institute (a BBSRC-supported, world-leading research centre for bioinformatics and genome biology) and UEA. The student will have access to training and career development opportunities at the UEA, the Earlham Institute, and onacross the Norwich Research Park as part of the Norwich Biosciences Doctoral Training Partnership.

References

Newman, T. J., Mamun, M. A., Nieduszynski, C. A. & Blow, J. J. Replisome stall events have shaped the distribution of replication origins in the genomes of yeasts. Nucleic Acids Res 41, 9705–9718 (2013)

Müller, C. A. et al. Capturing the dynamics of genome replication on individual ultra-long nanopore sequence reads. Nat Methods 16, 429–436 (2019)

Carrington, J. T. et al. Most human DNA replication initiation is dispersed throughout the genome with only a minority within previously identified initiation zones. bioRxiv 2024.04.28.591325 (2024) doi:10.1101/2024.04.28.591325

Ge, X. Q., Jackson, D. A. & Blow, J. J. Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes & Development 21, 3331–3341 (2007)

Moreno, A. et al. Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells. Proceedings of the National Academy of Sciences of the United States of America 113, E5757-64 (2016)