title: Processive DNA demethylation via DNA deaminase-induced lesion resolution.
abstract: Base modifications of cytosine are an important aspect of chromatin biology, as they can directly regulate gene expression, while DNA repair ensures that those modifications retain genome integrity. Here we characterize how cytosine DNA deaminase AID can initiate DNA demethylation. In vitro, AID initiated targeted DNA demethylation of methyl CpGs when in combination with DNA repair competent extracts. Mechanistically, this is achieved by inducing base alterations at or near methyl-cytosine, with the lesion being resolved either via single base substitution or a more efficient processive polymerase dependent repair. The biochemical findings are recapitulated in an in vivo transgenic targeting assay, and provide the genetic support of the molecular insight into DNA demethylation. This targeting approach supports the hypothesis that mCpG DNA demethylation can proceed via various pathways and mCpGs do not have to be targeted to be demethylated.
authors.affiliation: DNA Editing in Immunity and Epigenetics, IFOM-Fondazione Instituto FIRC di Oncologia Molecolare, Milano, Italy; DNA Editing Lab, Clare Hall Laboratories, London Research Institute, South Mimms, United Kingdom.
authors.forename: Don-Marc
authors.initials: DM
authors.lastname: Franchini
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Chun-Fung
authors.initials: CF
authors.lastname: Chan
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Morgan
authors.affiliation: DNA Editing in Immunity and Epigenetics, IFOM-Fondazione Instituto FIRC di Oncologia Molecolare, Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Incorvaia
authors.affiliation: DNA Editing in Immunity and Epigenetics, IFOM-Fondazione Instituto FIRC di Oncologia Molecolare, Milano, Italy; DNA Editing Lab, Clare Hall Laboratories, London Research Institute, South Mimms, United Kingdom.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Rangam
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Dean
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Fatima
authors.initials: F
authors.lastname: Santos
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.affiliation: DNA Editing in Immunity and Epigenetics, IFOM-Fondazione Instituto FIRC di Oncologia Molecolare, Milano, Italy; DNA Editing Lab, Clare Hall Laboratories, London Research Institute, South Mimms, United Kingdom.
authors.forename: Svend K
authors.initials: SK
authors.lastname: Petersen-Mahrt
mesh_terms: D000818:Animals; D018899:CpG Islands; D003564:Cytidine Deaminase / Q000378:metabolism*; D004249:DNA Damage; D019175:DNA Methylation; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D003564:Cytidine Deaminase