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PMID:17994007

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Citation

Sharif, J, Muto, M, Takebayashi, S, Suetake, I, Iwamatsu, A, Endo, TA, Shinga, J, Mizutani-Koseki, Y, Toyoda, T, Okamura, K, Tajima, S, Mitsuya, K, Okano, M and Koseki, H (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450:908-12

Abstract

DNA methyltransferase (cytosine-5) 1 (Dnmt1) is the principal enzyme responsible for maintenance of CpG methylation and is essential for the regulation of gene expression, silencing of parasitic DNA elements, genomic imprinting and embryogenesis. Dnmt1 is needed in S phase to methylate newly replicated CpGs occurring opposite methylated ones on the mother strand of the DNA, which is essential for the epigenetic inheritance of methylation patterns in the genome. Despite an intrinsic affinity of Dnmt1 for such hemi-methylated DNA, the molecular mechanisms that ensure the correct loading of Dnmt1 onto newly replicated DNA in vivo are not understood. The Np95 (also known as Uhrf1 and ICBP90) protein binds methylated CpG through its SET and RING finger-associated (SRA) domain. Here we show that localization of mouse Np95 to replicating heterochromatin is dependent on the presence of hemi-methylated DNA. Np95 forms complexes with Dnmt1 and mediates the loading of Dnmt1 to replicating heterochromatic regions. By using Np95-deficient embryonic stem cells and embryos, we show that Np95 is essential in vivo to maintain global and local DNA methylation and to repress transcription of retrotransposons and imprinted genes. The link between hemi-methylated DNA, Np95 and Dnmt1 thus establishes key steps of the mechanism for epigenetic inheritance of DNA methylation.

Links

PubMed Online version:10.1038/nature06397

Keywords

Animals; CpG Islands/genetics; DNA/chemistry; DNA/metabolism; DNA (Cytosine-5-)-Methyltransferase/metabolism; DNA Methylation; DNA Replication; Embryonic Stem Cells/metabolism; Epigenesis, Genetic; Genomic Imprinting; HeLa Cells; Heterochromatin/genetics; Heterochromatin/metabolism; Humans; Mice; Nuclear Proteins/chemistry; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Proliferating Cell Nuclear Antigen/metabolism; Protein Structure, Tertiary; Retroelements/genetics; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DNMT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8VDF2

F

Seeded From UniProt

complete

MOUSE:UHRF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P13864

F

Seeded From UniProt

complete

MOUSE:UHRF1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:UHRF1

involved_in

GO:0010216: maintenance of DNA methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:UHRF1

located_in

GO:0005657: replication fork

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:UHRF1

enables

GO:0044729: hemi-methylated DNA-binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:UHRF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:UHRF1

located_in

GO:0000792: heterochromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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