Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 20, Issue 10, Pages 1044-1050Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2012.41
Keywords
ICF syndrome; DNA replication; DNA methylation
Funding
- Fondation Jerome Lejeune
- Fondation pour la Recherche Medicale
- Saint Joseph University
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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. European Journal of Human Genetics (2012) 20, 1044-1050. doi: 10.1038/ejhg.2012.41; published online 29 February 2012
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