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Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease
- Source :
- Cell Reports, Vol 21, Iss 2, Pp 482-494 (2017)
- Publication Year :
- 2017
-
Abstract
- Summary: Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet dioxygenases reprograms genome function in embryogenesis and postnatal development. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or persist as durable marks, yet how these alternative fates are specified at individual CpGs is not understood. Here, we report that the SOS response-associated peptidase (SRAP) domain protein Srap1, the mammalian ortholog of an ancient protein superfamily associated with DNA damage response operons in bacteria, binds to Tet-oxidized forms of 5mC in DNA and catalyzes turnover of these bases to unmodified cytosine by an autopeptidase-coupled nuclease. Biallelic inactivation of murine Srap1 causes embryonic sublethality associated with widespread accumulation of ectopic 5hmC. These findings establish a function for a class of DNA base modification-selective nucleases and position Srap1 as a determinant of 5mC demethylation trajectories during mammalian embryonic development. : Kweon et al. uncover a function for the SRAP domain, which couples autoproteolytic cleavage to activation of a nuclease selective for DNA containing Tet-oxidized derivatives of 5-methylcytosine. These findings reveal a mechanism for targeted erasure of DNA methylation via the stepwise enzymatic actions of Tet and SRAP. Keywords: DNA methylation, Tet, SRAP, endonuclease, autopeptidase, embryonic stem cell
- Subjects :
- 0301 basic medicine
Male
DNA damage
Biology
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
chemistry.chemical_compound
Endonuclease
Mice
Animals
lcsh:QH301-705.5
Cells, Cultured
Embryonic Stem Cells
Nuclease
DNA Methylation
DNA-Binding Proteins
Mice, Inbred C57BL
5-Methylcytosine
030104 developmental biology
DNA demethylation
lcsh:Biology (General)
chemistry
Biochemistry
DNA methylation
biology.protein
Female
Cytosine
DNA
Protein Binding
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 21
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell reports
- Accession number :
- edsair.doi.dedup.....1d36da0997ec0180bd34663edf1f0620