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

doi:10.1038/s41467-018-06066-8

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^*

^*Corresponding author for this work

31 Citations (Scopus)

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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 language	English
Article number	3704
Journal	Nature Communications
Volume	9
Issue number	1
Pages (from-to)	1-11
Number of pages	11
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-06066-8
Publication status	Published - 2018

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Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensingFinal published version, 1.75 MBLicence: CC BY

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Shoaib, M., Walter, D., Gillespie, P. J., Izard, F., Fahrenkrog, B., Lleres, D., Lerdrup, M., Johansen, J. V., Hansen, K., Julien, E., Blow, J. J., & Sørensen, C. S. (2018). Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing. Nature Communications, 9(1), 1-11. Article 3704. https://doi.org/10.1038/s41467-018-06066-8

Shoaib, M, Walter, D, Gillespie, PJ, Izard, F, Fahrenkrog, B, Lleres, D, Lerdrup, M , Johansen, JV , Hansen, K, Julien, E, Blow, JJ & Sørensen, CS 2018, 'Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing', Nature Communications, vol. 9, no. 1, 3704, pp. 1-11. https://doi.org/10.1038/s41467-018-06066-8

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title = "Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing",

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.",

author = "Muhammad Shoaib and David Walter and Gillespie, {Peter J.} and Fanny Izard and Birthe Fahrenkrog and David Lleres and Mads Lerdrup and Johansen, {Jens Vilstrup} and Klaus Hansen and Eric Julien and Blow, {J. Julian} and S{\o}rensen, {Claus S.}",

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AU - Shoaib, Muhammad

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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.

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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.

U2 - 10.1038/s41467-018-06066-8

DO - 10.1038/s41467-018-06066-8

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

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