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Sci Rep. 2019 Jul 30;9(1):11065. doi: 10.1038/s41598-019-47528-3.

5-hydroxymethylcytosine Marks Mammalian Origins Acting as a Barrier to Replication.

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Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway.
Institute of Basic Medical Sciences, University of Oslo, PO Box 1018 Blindern, N-0315, Oslo, Norway.
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, 0379, Oslo, Norway.
Proteomics and Metabolomics Core Facility, Norwegian University of Science and Technology, 7491, Trondheim, Norway.
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, Montebello, 0379, Oslo, Norway.
The Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway.
Hemispherian AS, Gaustadalleen 21, 0349, Oslo, Norway.


In most mammalian cells, DNA replication occurs once, and only once between cell divisions. Replication initiation is a highly regulated process with redundant mechanisms that prevent errant initiation events. In lower eukaryotes, replication is initiated from a defined consensus sequence, whereas a consensus sequence delineating mammalian origin of replication has not been identified. Here we show that 5-hydroxymethylcytosine (5hmC) is present at mammalian replication origins. Our data support the hypothesis that 5hmC has a role in cell cycle regulation. We show that 5hmC level is inversely proportional to proliferation; indeed, 5hmC negatively influences cell division by increasing the time a cell resides in G1. Our data suggest that 5hmC recruits replication-licensing factors, then is removed prior to or during origin firing. Later we propose that TET2, the enzyme catalyzing 5mC to 5hmC conversion, acts as barrier to rereplication. In a broader context, our results significantly advance the understating of 5hmC involvement in cell proliferation and disease states.

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