A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

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.; Sorensen, C. S.

doi:10.1101/350033

bioRxiv · 10.1101/350033

A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

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.·Sorensen, C. S.

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Abstract

The decompaction and re-establishment of chromatin organization immediately after mitosis is essential for genome regulation. The 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, appropriate chromatin relaxation is safeguarded by SET8-dependent methylation of histone H4 on lysine 20. Thus, in the absence of either SET8 or the H4K20 residue, substantial genome-wide chromatin decompaction occurs which allows 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 the 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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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., Sorensen, C. S.. 2018-06-27. A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing. https://doi.org/10.1101/350033

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