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  Discovering how DNA replication errors cause cancer chromosomal instability

   London Interdisciplinary Biosciences Consortium (LIDo)

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  Dr S McClelland, Dr H Robinson  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this project please visit the LIDo website:

AIM: To employ a novel set of state-of-the-art DNA sequencing technologies (including single cell, and single molecule approaches) to dissect the precise impact on the genome of specific deregulated DNA damage repair processes.


Replication stress is a known driver of human pathologies including aging and cancer, but exact cellular mechanisms involved remain unclear and targeting replication stress therapeutically is still a challenge. Cancer carries a higher intrinsic level of replication stress compared to normal cells. This increase can theoretically be exploited, however this approach is subject to attaining a precise threshold to avoid toxicity to normal cells. Therefore, to increase specificity for cancer-specific cell killing we are searching for specific mechanistic differences between cancer and normal cells in how they tolerate or repair replication stress and the ensuing chromosomal instability. Various DNA repair pathways exist to deal with, or bypass replication stress. However the relative use of these in cancer cells which often carry mutations in these pathways is not known. We will determine the genetic signature of specific defects in replication stress repair in cancer by using a combination of single cell copy number alteration (CNA) analysis, and newly developed single molecule experiments (targeted long-read sequencing).

Artios Pharma lead the field in development of new pharmacological agents targeting the DNA damage response and have recently brought a novel polymerase Theta inhibitor to clinical trials, where it can synergise with homologous recombination defects such as those caused by BRCA gene mutations. The McClelland laboratory, meanwhile, have pioneered the use of single cell and single molecule sequencing methods to unpick mechanisms of replication stress and genomic instability in cancer, and have a wealth of experience and research tools in the field of ovarian cancer, where replication stress, and homologous recombination defects are rife. Together our expertise provides an ideal test bed to dissect mechanisms and sensitivities of cancer replication stress.

To apply for this project please visit the LIDo website:

Biological Sciences (4)

Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,609.
LIDo has a maximum of 11 fully funded opportunities for students eligible for overseas fees.


• N. Tamura, N. Shaikh, D. Muliaditan, J. McGuinness, D. Moralli, M. A. Durin, C. M. Green, D. Bowtell, F. R. Balkwill, K. Curtius, McClelland SE†. Specific mechanisms of chromosomal instability indicate therapeutic sensitivities in high-grade serous ovarian carcinoma. Cancer Research 2020
• A. Mazzagatti, N. Shaikh, B. Bakker, D. Muliaditan, D.C.J. Spierings, F. Foijer, M..A. Boemo, S.E. McClelland†. Replication stress generates multiple distinct classes of DNA copy number alteration. Under revision at Genome Biology; BioRXiv 2020
• Worrall JT, Tamura N, Mazzagatti A, Shaikh N, van Lingen T, Bakker B, Spierings DCJ, Vladimirou E, Foijer F, McClelland S.E.†. Non-random Mis-segregation of Human Chromosomes. Cell Rep. 2018
• Burrell RA*, McClelland S.E.*, …. Swanton C. Replication stress links structural and numerical chromosomal instability in colorectal cancer. Nature. 2013
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