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H4 K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex

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Title: H4 K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex
Authors: Saredi, G
Huang, H
Hammond, CH
Alabert, C
Bekker-Jensen, S
Forne, I
Reverón-Gómez, N
Foster, BM
Mlejnkova, L
Bartke, T
Cejka, P
Mailand, N
Imhof, A
Patel, DJ
Groth, A
Item Type: Journal Article
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 postreplicative states locally remain unknown. Here, we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the TONSL–MMS22L1-4 homologous recombination (HR) 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 G2/M. Accordingly, TONSL–MMS22L binds new histones H3–H4 both prior to 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, this reveals a histone reader based mechanism to recognize the post-replicative state, offering a new approach and opportunity to understand DNA repair with potential for targeted cancer therapy.
Issue Date: 22-Jun-2016
Date of Acceptance: 5-May-2016
URI: http://hdl.handle.net/10044/1/32843
DOI: https://dx.doi.org/10.1038/nature18312
ISSN: 0028-0836
Publisher: Nature Publishing Group
Start Page: 714
End Page: 718
Journal / Book Title: Nature
Volume: 534
Copyright Statement: © 2016 Macmillan Publishers Limited. All rights reserved.
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 309952
Keywords: Chromatin
DNA Repair
DNA Replication
DNA-Binding Proteins
Genomic Instability
Histones
Homologous Recombination
Humans
Lysine
Methylation
Models, Molecular
Molecular Chaperones
NF-kappa B
Nuclear Proteins
Protein Binding
Protein Structure, Tertiary
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Appears in Collections:Institute of Clinical Sciences