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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Damage / genetics
  • DNA Damage / physiology
  • DNA Replication / genetics
  • DNA Replication / physiology*
  • Flow Cytometry
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Microscopy, Fluorescence
  • RNA, Small Interfering / genetics

Substances

  • Chromatin
  • Histones
  • RNA, Small Interfering