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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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Details
1 Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
2 Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway
3 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway
4 Proteomics and Metabolomics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway
5 Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Norway; Proteomics and Metabolomics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway
6 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, Montebello, Oslo, Norway; 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; Hemispherian AS, Gaustadalleen 21, Oslo, Norway