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

TY - JOUR

T1 - Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

AU - Shoaib, Muhammad

AU - Walter, David

AU - Gillespie, Peter J.

AU - Izard, Fanny

AU - Fahrenkrog, Birthe

AU - Lleres, David

AU - Lerdrup, Mads

AU - Johansen, Jens Vilstrup

AU - Hansen, Klaus

AU - Julien, Eric

AU - Blow, J. Julian

AU - Sørensen, Claus S.

N1 - C.S.S., M.S., and D.W. are funded by The Novo Nordisk Foundation (to C.S.S.), The Danish Cancer Society (to C.S.S.), The Lundbeck Foundation (to C.S.S.), and The Danish Medical Research Council (to C.S.S.), Swiss National Science Foundation (to D.W.), and Villum Foundation (to M.S.). B.F. is funded by FNRS Belgium and P.J.G. and J.J.B. are funded by Cancer Research UK (grant C303/A14301). F.I. and E.J. were supported by grants from French Plan-Cancer (EPIG2013-13), Labex EpiGenMed, and SIRIC Montpellier Cancer. F.I. was supported by a PhD fellowship from the French Ligue Contre le Cancer and Fondation pour la Recherche Médicale. D.L. was supported by a Cancéropole GSO-Emergence grant (2014-E17) and CNRS.

PY - 2018/9/12

Y1 - 2018/9/12

N2 - 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.

AB - 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.

KW - MRI 3D visualization

KW - MRI images

KW - Medical image processing

KW - Medical imaging

KW - Tumor segmentation and classification

U2 - 10.1038/s41467-018-06066-8

DO - 10.1038/s41467-018-06066-8

M3 - Article

C2 - 30209253

SN - 2041-1723

VL - 9

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3704

ER -