title: H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex.
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.
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Giulia
authors.initials: G
authors.lastname: Saredi
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Hongda
authors.initials: H
authors.lastname: Huang
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Colin M
authors.initials: CM
authors.lastname: Hammond
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Constance
authors.initials: C
authors.lastname: Alabert
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Forne
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Nazaret
authors.initials: N
authors.lastname: Reverón-Gómez
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, United Kingdom.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Foster
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Switzerland.
authors.forename: Lucie
authors.initials: L
authors.lastname: Mlejnkova
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, United Kingdom.
authors.forename: Till
authors.initials: T
authors.lastname: Bartke
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Switzerland.
authors.forename: Petr
authors.initials: P
authors.lastname: Cejka
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
authors.affiliation: Department of Molecular Biology, Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Groth
mesh_terms: D002843:Chromatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042822:Genomic Instability; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D059765:Homologous Recombination; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C554517:MMS22L protein, human; D018832:Molecular Chaperones; D016328:NF-kappa B; D009687:Nuclear Proteins; C093394:TONSL protein, human; D008239:Lysine