title: Chromatin determinants of the inner-centromere rely on replication factors with functions that impart cohesion.
abstract: Replication fork-associated factors promote genome integrity and protect against cancer. Mutations in the DDX11 helicase and the ESCO2 acetyltransferase also cause related developmental disorders classified as cohesinopathies. Here we generated vertebrate model cell lines of these disorders and cohesinopathies-related genes. We found that vertebrate DDX11 and Tim-Tipin are individually needed to compensate for ESCO2 loss in chromosome segregation, with DDX11 also playing complementary roles with ESCO2 in centromeric cohesion. Our study reveals that overt centromeric cohesion loss does not necessarily precede chromosome missegregation, while both these problems correlate with, and possibly originate from, inner-centromere defects involving reduced phosphorylation of histone H3T3 (pH3T3) in the region. Interestingly, the mitotic pH3T3 mark was defective in all analyzed replication-related mutants with functions in cohesion. The results pinpoint mitotic pH3T3 as a postreplicative chromatin mark that is sensitive to replication stress and conducts with different kinetics to robust centromeric cohesion and correct chromosome segregation.
authors.affiliation: IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
authors.forename: Takuya
authors.initials: T
authors.lastname: Abe
authors.affiliation: IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.|Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Minamiosawa, Hachioji-shi, Tokyo, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Kawasumi
authors.affiliation: IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hori
authors.affiliation: Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi Bunkyo-Ku, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.affiliation: Chromosome Dynamics Group, Molecular Oncology Program, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Losada
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Fukagawa
authors.affiliation: IFOM, The FIRC Institute for Molecular Oncology Foundation, Milan, Italy.
authors.forename: Dana
authors.initials: D
authors.lastname: Branzei
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D002503:Centromere / Q000235:genetics* / Q000378:metabolism; D002645:Chickens; D002842:Chromatids / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D004480:Ectromelia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006972:Hypertelorism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000235:genetics
chemical_list: D030161:Avian Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D000123:Acetyltransferases; C500785:ESCO2 protein, human; D004265:DNA Helicases; C101830:DDX11 protein, human; D053487:DEAD-box RNA Helicases
keywords: DDX11; Tim-Tipin; inner-centromere; replication stress; sister chromatid cohesion; Chromosome Section