title: DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations.
abstract: ICF syndrome is a rare autosomal recessive disorder that is characterized by Immunodeficiency, Centromeric instability, and Facial anomalies. In all, 60% of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In ICF cells, constitutive heterochromatin is hypomethylated and decondensed, metaphase chromosomes undergo rearrangements (mainly involving juxtacentromeric regions), and more than 700 genes are aberrantly expressed. This work shows that DNA replication is also altered in ICF cells: (i) heterochromatic genes replicate earlier in the S-phase; (ii) global replication fork speed is higher; and (iii) S-phase is shorter. These replication defects may result from chromatin changes that modify DNA accessibility to the replication machinery and/or from changes in the expression level of genes involved in DNA replication. This work highlights the interest of using ICF cells as a model to investigate how DNA methylation regulates DNA replication in humans.
authors.affiliation: INSERM U827, av. du Doyen Gaston Giraud, Montpellier, France.
authors.forename: Erica
authors.initials: E
authors.lastname: Lana
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Hélène
authors.initials: H
authors.lastname: Tourrière
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Gérard
authors.initials: G
authors.lastname: Lefranc
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Albertina
authors.initials: A
authors.lastname: De Sario
mesh_terms: D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D005145:Face / Q000002:abnormalities; D015870:Gene Expression; D006570:Heterochromatin / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D020125:Mutation, Missense; D000081207:Primary Immunodeficiency Diseases; D016196:S Phase / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D006570:Heterochromatin; D000097584:DNA Methyltransferase 3B