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Nat Commun. 2018 Sep 12;9(1):3704. doi: 10.1038/s41467-018-06066-8.

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

Author information

1
Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
2
Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
3
Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, University of Montpellier, Institut Régional du Cancer (ICM), F-34298, Montpellier, France.
4
Institute for Molecular Biology and Medicine, Universite Libré de Bruxelles, Charleroi, 6041, Belgium.
5
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, 34293, France.
6
Centre National de la Recherche Scientifique (CNRS), Montpellier, 34000, France.
7
Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark. claus.storgaard@bric.ku.dk.

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.

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