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Sci Rep ; 9(1): 11065, 2019 07 30.
Article in English | MEDLINE | ID: mdl-31363131

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.


Subject(s)
5-Methylcytosine/analogs & derivatives , Cell Cycle/genetics , Cell Division/physiology , Cell Proliferation/physiology , DNA Replication/physiology , 5-Methylcytosine/metabolism , HeLa Cells , Humans , Replication Origin
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