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Nature. 2016 Jun 30;534(7609):714-718. doi: 10.1038/nature18312. Epub 2016 Jun 22.

H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex.

Author information

1
Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
2
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
3
The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark.
4
Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Munich, Germany.
5
MRC Clinical Sciences Centre, Imperial College London, United Kingdom.
6
Institute of Molecular Cancer Research, University of Zurich, Switzerland.
#
Contributed equally

Abstract

After DNA replication, chromosomal processes including DNA repair and transcription take place in the context of sister chromatids. While cell cycle regulation can guide these processes globally, mechanisms to distinguish pre- and post-replicative states locally remain unknown. Here we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL–MMS22L homologous recombination complex. We identify the TONSL ankyrin repeat domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until the G2/M phase of the cell cycle. Accordingly, TONSL–MMS22L binds new histones H3–H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M. H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability and resistance to replication stress. Together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy.

PMID:
27338793
PMCID:
PMC4939875
DOI:
10.1038/nature18312
[Indexed for MEDLINE]
Free PMC Article
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