Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

Muhammad Shoaib, David Walter, Peter J. Gillespie, Fanny Izard, Birthe Fahrenkrog, David Lleres, Mads Lerdrup, Jens Vilstrup Johansen, Klaus Hansen, Eric Julien, J. Julian Blow, Claus S. Sørensen (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    63 Citations (Scopus)
    164 Downloads (Pure)

    Abstract

    The decompaction and re-establishment of chromatin organization immediately after mitosis is essential for genome regulation. Mechanisms underlying chromatin structure control in daughter cells are not fully understood. Here we show that a chromatin compaction threshold in cells exiting mitosis ensures genome integrity by limiting replication licensing in G1 phase. Upon mitotic exit, chromatin relaxation is controlled by SET8-dependent methylation of histone H4 on lysine 20. In the absence of either SET8 or H4K20 residue, substantial genome-wide chromatin decompaction occurs allowing excessive loading of the origin recognition complex (ORC) in the daughter cells. ORC overloading stimulates aberrant recruitment of the MCM2-7 complex that promotes single-stranded DNA formation and DNA damage. Restoring chromatin compaction restrains excess replication licensing and loss of genome integrity. Our findings identify a cell cycle-specific mechanism whereby fine-tuned chromatin relaxation suppresses excessive detrimental replication licensing and maintains genome integrity at the cellular transition from mitosis to G1 phase.

    Original languageEnglish
    Article number3704
    Pages (from-to)1-11
    Number of pages11
    JournalNature Communications
    Volume9
    Issue number1
    DOIs
    Publication statusPublished - 12 Sept 2018

    Keywords

    • MRI 3D visualization
    • MRI images
    • Medical image processing
    • Medical imaging
    • Tumor segmentation and classification

    ASJC Scopus subject areas

    • Software
    • Media Technology
    • Hardware and Architecture
    • Computer Networks and Communications

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