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Cell. 2016 Dec 15;167(7):1774-1787.e13. doi: 10.1016/j.cell.2016.11.009. Epub 2016 Dec 1.

A Surveillance Mechanism Ensures Repair of DNA Lesions during Zygotic Reprogramming.

Author information

1
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter, Dr. Bohr-Gasse 3, Vienna 1030, Austria.
2
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.

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.

KEYWORDS:

DNA damage repair; checkpoint; cohesin; reprogramming; zygote

PMID:
27916276
PMCID:
PMC5161750
DOI:
10.1016/j.cell.2016.11.009
[Indexed for MEDLINE]
Free PMC Article

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