Work

Human DNA replication initiation sites are specified epigenetically by oxidation of 5-methyl-deoxycytidine.

Year: 2025

Type: article

Abstract: DNA replication initiates at tens of thousands of sites on the human genome during each S phase. However, no consensus DNA sequence has been found that specifies the locations of these replication origins. Here, we investigate modifications of human genomic DNA by density equilibrium centrifugation and DNA sequencing. We identified short discrete sites with increased density during quiescence and G1 phase that overlap with DNA replication origins before their activation in S phase. The increased density is due to the oxidation of 5-methyl-deoxycytidines by ten-eleven-translocation DNA dioxygenase (TET) enzymes at GC-rich domains. Reversible inhibition of de novo methylation and of subsequent oxidation of deoxycytidines results in a reversible inhibition of DNA replication and of cell proliferation. Our findings suggest a mechanism for the epigenetic specification and semiconservative inheritance of DNA replication origin sites in human cells that also provides a stable integral DNA replication licence to support once-per-cell cycle control of origin activation.

Source: Apollo (University of Cambridge)

DOI: 10.17863/cam.117777

Authors: Krude, Torsten, Bi, Jiaming, Doran, Rachel, Jones, Rebecca A, Smith, James C

Language: English

Topic: Epigenetics and DNA Methylation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funder: Wellcome Trust

Award: A multi-user facility for cell imaging and manipulation.

OpenAlex ID: W6963149600

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