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Stimulation of adaptive gene amplification by origin firing under replication fork constraint

View ORCID ProfileAlex J. Whale, View ORCID ProfileMichelle King, View ORCID ProfileRyan M. Hull, View ORCID ProfileFelix Krueger, View ORCID ProfileJonathan Houseley
doi: https://doi.org/10.1101/2021.03.04.433911
Alex J. Whale
1Epigenetics Programme, Babraham Institute, Cambridge, United Kingdom
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Michelle King
3Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
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Ryan M. Hull
5SciLifeLab, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
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Felix Krueger
6Babraham Bioinformatics, Babraham Institute, Cambridge, United Kingdom
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Jonathan Houseley
1Epigenetics Programme, Babraham Institute, Cambridge, United Kingdom
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  • For correspondence: jon.houseley@babraham.ac.uk
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Abstract

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32, factors known to alter the frequency of template switching during break induced replication (BIR). CUP1 amplification is also critically dependent on late firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after firing, leaving an epigenetic scar of H3K56 acetylation that promotes template switching during later break induced replication events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 04, 2021.
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Stimulation of adaptive gene amplification by origin firing under replication fork constraint
Alex J. Whale, Michelle King, Ryan M. Hull, Felix Krueger, Jonathan Houseley
bioRxiv 2021.03.04.433911; doi: https://doi.org/10.1101/2021.03.04.433911
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Stimulation of adaptive gene amplification by origin firing under replication fork constraint
Alex J. Whale, Michelle King, Ryan M. Hull, Felix Krueger, Jonathan Houseley
bioRxiv 2021.03.04.433911; doi: https://doi.org/10.1101/2021.03.04.433911

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