title: Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway.
abstract: Genome-wide active DNA demethylation in primordial germ cells (PGCs), which reprograms the epigenome for totipotency, is linked to changes in nuclear architecture, loss of histone modifications, and widespread histone replacement. Here, we show that DNA demethylation in the mouse PGCs is mechanistically linked to the appearance of single-stranded DNA (ssDNA) breaks and the activation of the base excision repair (BER) pathway, as is the case in the zygote where the paternal pronucleus undergoes active DNA demethylation shortly after fertilization. Whereas BER might be triggered by deamination of a methylcytosine (5mC), cumulative evidence indicates other mechanisms in germ cells. We demonstrate that DNA repair through BER represents a core component of genome-wide DNA demethylation in vivo and provides a mechanistic link to the extensive chromatin remodeling in developing PGCs.
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.|MRC Clinical Sciences Centre, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Hajkova
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Jeffries
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Miller
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: M Azim
authors.initials: MA
authors.lastname: Surani
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D053904:DNA Breaks, Single-Stranded; D019175:DNA Methylation; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D016678:Genome; D005854:Germ Cells / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1; D015053:Zygote / Q000187:drug effects / Q000378:metabolism
chemical_list: C503406:7-nitro-1H-indole-2-carboxylic acid; D001549:Benzamides; D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006657:Histones; D007211:Indoles; D000076105:X-ray Repair Cross Complementing Protein 1; D011064:Poly Adenosine Diphosphate Ribose; C025160:3-aminobenzamide