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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.

Author information

1
Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway.
2
Institute of Basic Medical Sciences, University of Oslo, PO Box 1018 Blindern, N-0315, Oslo, Norway.
3
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, 0379, Oslo, Norway.
4
Proteomics and Metabolomics Core Facility, Norwegian University of Science and Technology, 7491, Trondheim, Norway.
5
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, Montebello, 0379, Oslo, Norway.
6
The Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
7
Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway. adam.robertson@hemispherian.com.
8
Hemispherian AS, Gaustadalleen 21, 0349, Oslo, Norway. adam.robertson@hemispherian.com.

Abstract

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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