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. 2018 Sep 18;8:14012. doi: 10.1038/s41598-018-32356-8

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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The proposed model that connects AHCY activity, DNA damage and the regulation of the cell cycle through adenosine levels in hepatocellular carcinoma cells. Left: General schematic representation of proposed model: lowered AHCY activity causes adenosine depletion, stalling of replication forks and subsequent DNA damage, which activates various signalling pathways and causes cell cycle arrest in the G1/S checkpoint. Strong and sudden lowering of the AHCY activity causes immediate proliferation changes in cancer cells; however, mild inactivation of AHCY would cause chronic stress for liver cells and thus contribute to adult onset liver disease, such as hepatocellular carcinoma as observed in the latest case of AHCY deficiency. Right: A detailed overview of how adenosine depletion could cause replication fork stalling through misbalance of the dNTP pool due to lower dATP levels, and subsequent impairment of adequate rates of DNA synthesis and progression of the replication forks. Treatment with hydroxyurea, although following another pathway, facilitates a similar and well-described effect through the disturbance of the balance of the total dNTP pool.