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Aberrant replication licensing drives Copy Number Gains across species

View ORCID ProfilePatroula Nathanailidou, Michalis Petropoulos, Styliani Maxouri, Eirini Kasselimi, Ioanna Eleni Symeonidou, Ourania Preza, Iris Spiliopoulou-Sdougkou, Vladimir Beneš, Stavros Taraviras, Zoi Lygerou
doi: https://doi.org/10.1101/2020.10.10.334516
Patroula Nathanailidou
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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  • ORCID record for Patroula Nathanailidou
Michalis Petropoulos
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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Styliani Maxouri
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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Eirini Kasselimi
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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Ioanna Eleni Symeonidou
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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Ourania Preza
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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Iris Spiliopoulou-Sdougkou
2Department of Microbiology, School of Medicine, University of Patras, Patras 26504, Greece
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Vladimir Beneš
3Genomics Core Facility, European Molecular Biology Laboratory, 69117, Heidelberg, Germany
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Stavros Taraviras
4Department of Physiology, School of Medicine, University of Patras, Patras 26504, Greece
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Zoi Lygerou
1Department of General Biology, School of Medicine, University of Patras, Patras 26504, Greece
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  • For correspondence: lygerou@med.upatras.gr
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Abstract

Copy Number Gains (CNGs) lead to genetic heterogeneity, driving evolution and carcinogenesis. The mechanisms promoting CNG formation however remain poorly characterized. We show that abnormal expression of the replication licensing factor Cdc18 in fission yeast, which leads to genome-wide re-replication, drives the formation of CNGs at different genomic loci, promoting the acquisition of new selectable traits. Whole genome sequencing reveals Mb long, primarily extrachromosomal amplicons. Genetic analysis shows that homology-mediated repair is required to resolve re-replication intermediates into heritable CNGs. Consistently, we show that in mammalian cells overexpression of CDC6 and/or CDT1 leads to CNGs and promotes drug resistance. In human cells, multiple repair pathways are activated upon rereplication and act antagonistically, with RAD52 promoting and 53BP1 inhibiting CNG formation. In tumours, CDT1 and/or CDC6 overexpression correlates with copy number gains genome-wide. We propose re-replication as an evolutionary-conserved driver of CNGs, highlighting a link between aberrant licensing, CNGs and cancer.

Competing Interest Statement

The authors have declared no competing interest.

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Posted October 10, 2020.
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Aberrant replication licensing drives Copy Number Gains across species
Patroula Nathanailidou, Michalis Petropoulos, Styliani Maxouri, Eirini Kasselimi, Ioanna Eleni Symeonidou, Ourania Preza, Iris Spiliopoulou-Sdougkou, Vladimir Beneš, Stavros Taraviras, Zoi Lygerou
bioRxiv 2020.10.10.334516; doi: https://doi.org/10.1101/2020.10.10.334516
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Aberrant replication licensing drives Copy Number Gains across species
Patroula Nathanailidou, Michalis Petropoulos, Styliani Maxouri, Eirini Kasselimi, Ioanna Eleni Symeonidou, Ourania Preza, Iris Spiliopoulou-Sdougkou, Vladimir Beneš, Stavros Taraviras, Zoi Lygerou
bioRxiv 2020.10.10.334516; doi: https://doi.org/10.1101/2020.10.10.334516

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