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3D chromatin connectivity underlies replication origin efficiency in mouse embryonic stem cells.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
    • Publication Information:
      Publication: 1992- : Oxford : Oxford University Press
      Original Publication: London, Information Retrieval ltd.
    • Subject Terms:
      Replication Origin*/genetics ; Chromatin*/genetics; Animals ; Mice ; Mouse Embryonic Stem Cells/metabolism ; DNA Replication/genetics ; Cell Cycle Proteins/metabolism ; Mammals/genetics
    • Abstract:
      In mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled. Replicative stress triggers additional initiation events from 'dormant' origins whose genomic distribution and regulation are not well understood. In this study, we have analyzed origin activity in mouse embryonic stem cells in the absence or presence of mild replicative stress induced by aphidicolin, a DNA polymerase inhibitor, or by deregulation of origin licensing factor CDC6. In both cases, we observe that the majority of stress-responsive origins are also active in a small fraction of the cell population in a normal S phase, and stress increases their frequency of activation. In a search for the molecular determinants of origin efficiency, we compared the genetic and epigenetic features of origins displaying different levels of activation, and integrated their genomic positions in three-dimensional chromatin interaction networks derived from high-depth Hi-C and promoter-capture Hi-C data. We report that origin efficiency is directly proportional to the proximity to transcriptional start sites and to the number of contacts established between origin-containing chromatin fragments, supporting the organization of origins in higher-level DNA replication factories.
      (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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    • Accession Number:
      0 (Chromatin)
      0 (Cell Cycle Proteins)
    • Publication Date:
      Date Created: 20221201 Date Completed: 20221220 Latest Revision: 20221223
    • Publication Date:
      20250114
    • Accession Number:
      PMC9757045
    • Accession Number:
      10.1093/nar/gkac1111
    • Accession Number:
      36453993