title: H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing.
abstract: DNA replication is a tightly regulated process that initiates from multiple replication origins and leads to the faithful transmission of the genetic material. For proper DNA replication, the chromatin surrounding origins needs to be remodeled. However, remarkably little is known on which epigenetic changes are required to allow the firing of replication origins. Here, we show that the histone demethylase KDM5C/JARID1C is required for proper DNA replication at early origins. JARID1C dictates the assembly of the pre-initiation complex, driving the binding to chromatin of the pre-initiation proteins CDC45 and PCNA, through the demethylation of the histone mark H3K4me3. Fork activation and histone H4 acetylation, additional early events involved in DNA replication, are not affected by JARID1C downregulation. All together, these data point to a prominent role for JARID1C in a specific phase of DNA replication in mammalian cells, through its demethylase activity on H3K4me3.
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Molecular Medicine PhD Program, Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milan, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Rondinelli
authors.affiliation: Laboratory of Stem Cell and Genome Plasticity in Development and Aging, Institute of Regenerative Medicine and Biotherapies, INSERM U1183, Montpellier University, Montpellier, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Schwerer
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Antonini
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Molecular Medicine PhD Program, Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gaviraghi
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Molecular Medicine PhD Program, Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lupi
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Frenquelli
authors.affiliation: Centre for Translational Genomics and Bioinformatics, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Segalla
authors.affiliation: Laboratory of Stem Cell and Genome Plasticity in Development and Aging, Institute of Regenerative Medicine and Biotherapies, INSERM U1183, Montpellier University, Montpellier, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lemaitre
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy tonon.giovanni@hsr.it.
authors.forename: Giovanni
authors.identifier: http://orcid.org/0000-0003-2973-5038
authors.initials: G
authors.lastname: Tonon
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D006367:HeLa Cells; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D018741:Replication Origin; D013997:Time Factors
chemical_list: C113571:CDC45 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D018809:Proliferating Cell Nuclear Antigen; D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine