5-hydroxymethylcytosine marks mammalian origins acting as a barrier to replication
Prikrylova, Terezia; Robertson, Julia; Ferrucci, Francesca; Konorska, Dorota Joanna; Aanes, Håvard; Manaf, Adeel; Zhang, Beibei; Vågbø, Cathrine Broberg; Kusnierczyk, Anna; Gilljam, Karin Margaretha; Løvkvam-Køster, Caroline; Otterlei, Marit; Dahl, John Arne; Enserink, Jorrit; Klungland, Arne; Robertson, Adam Brian
Journal article, Peer reviewed
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Original versionScientific Reports. 2019, 9:11065 1-16. 10.1038/s41598-019-47528-3
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.