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SAMHD1 promotes oncogene-induced replication stress

View ORCID ProfileSi Min Zhang, View ORCID ProfileJose M Calderón-Montaño, View ORCID ProfileSean G Rudd
doi: https://doi.org/10.1101/2020.07.29.226282
Si Min Zhang
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Jose M Calderón-Montaño
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Sean G Rudd
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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  • For correspondence: sean.rudd@scilifelab.se
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Abstract

Oncogenes induce DNA replication stress in cancer cells. Although this was established more than a decade ago, we are still unravelling the molecular underpinnings of this phenomenon, which will be critical if we are to exploit this knowledge to improve cancer treatment. A key mediator of oncogene-induced replication stress is the availability of DNA precursors, which will limit ongoing DNA synthesis by cellular replicases. In this study, we identify a potential role for nucleotide catabolism in promoting replication stress induced by oncogenes. Specifically, we establish that the dNTPase SAMHD1 slows DNA replication fork speeds in human fibroblasts harbouring an oncogenic RAS allele, elevating levels of endogenous DNA damage, and ultimately limiting cell proliferation. We then show that oncogenic RAS-driven tumours express reduced SAMHD1 levels, suggesting they have overcome this tumour suppressor barrier, and that this correlates with worse overall survival for these patients.

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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 July 29, 2020.
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SAMHD1 promotes oncogene-induced replication stress
Si Min Zhang, Jose M Calderón-Montaño, Sean G Rudd
bioRxiv 2020.07.29.226282; doi: https://doi.org/10.1101/2020.07.29.226282
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SAMHD1 promotes oncogene-induced replication stress
Si Min Zhang, Jose M Calderón-Montaño, Sean G Rudd
bioRxiv 2020.07.29.226282; doi: https://doi.org/10.1101/2020.07.29.226282

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