title: A Surveillance Mechanism Ensures Repair of DNA Lesions during Zygotic Reprogramming.
abstract: Sexual reproduction culminates in a totipotent zygote with the potential to produce a whole organism. Sperm chromatin reorganization and epigenetic reprogramming that alter DNA and histone modifications generate a totipotent embryo. Active DNA demethylation of the paternal genome has been proposed to involve base excision and DNA repair-based mechanisms. The nature and consequence of DNA lesions generated during reprogramming are not known. Using mouse genetics and chemical biology, we discovered that Tet3-dependent zygotic reprogramming generates paternal DNA lesions that are monitored by a surveillance mechanism. In vivo structure-function rescue assays revealed that cohesin-dependent repair of paternal DNA lesions prevents activation of a Chk1-dependent checkpoint that delays mitotic entry. Culturing conditions affect checkpoint stringency, which has implications for human in vitro fertilization. We propose the zygotic checkpoint senses DNA lesions generated during paternal DNA demethylation and ensures reprogrammed loci are repaired before mitosis to prevent chromosome fragmentation, embryo loss, and infertility.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter, Dr. Bohr-Gasse 3, Vienna 1030, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ladstätter
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter, Dr. Bohr-Gasse 3, Vienna 1030, Austria. Electronic address: kikue.tachibana@imba.oeaw.ac.at.
authors.forename: Kikuë
authors.initials: K
authors.lastname: Tachibana-Konwalski
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D065150:Cellular Reprogramming; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1; D015053:Zygote / Q000166:cytology* / Q000378:metabolism*; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D000097722:Cohesins; C465862:Rad21 protein, mouse; C551915:Tet3 protein, mouse
keywords: DNA damage repair; checkpoint; cohesin; reprogramming; zygote