The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA - PubMed (original) (raw)

. 2007 Dec 6;450(7171):908-12.

doi: 10.1038/nature06397. Epub 2007 Nov 11.

Masahiro Muto, Shin-ichiro Takebayashi, Isao Suetake, Akihiro Iwamatsu, Takaho A Endo, Jun Shinga, Yoko Mizutani-Koseki, Tetsuro Toyoda, Kunihiro Okamura, Shoji Tajima, Kohzoh Mitsuya, Masaki Okano, Haruhiko Koseki

Affiliations

• PMID: 17994007
• DOI: 10.1038/nature06397

The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA

Jafar Sharif et al. Nature. 2007.

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.

PubMed Disclaimer

Similar articles

• Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism.
  Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M. Arita K, et al. Nature. 2008 Oct 9;455(7214):818-21. doi: 10.1038/nature07249. Epub 2008 Sep 3. Nature. 2008. PMID: 18772891
• Biological functions of DNA methyltransferase 1 require its methyltransferase activity.
  Damelin M, Bestor TH. Damelin M, et al. Mol Cell Biol. 2007 Jun;27(11):3891-9. doi: 10.1128/MCB.00036-07. Epub 2007 Mar 19. Mol Cell Biol. 2007. PMID: 17371843 Free PMC article.
• Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors.
  Sharif J, Koseki H. Sharif J, et al. Prog Mol Biol Transl Sci. 2011;101:289-310. doi: 10.1016/B978-0-12-387685-0.00008-1. Prog Mol Biol Transl Sci. 2011. PMID: 21507355 Review.
• Epigenetic programming of differential gene expression in development and evolution.
  Monk M. Monk M. Dev Genet. 1995;17(3):188-97. doi: 10.1002/dvg.1020170303. Dev Genet. 1995. PMID: 8565325 Review.

Cited by

• 5-Hydroxymethylcytosine: Far Beyond the Intermediate of DNA Demethylation.
  Zheng K, Lyu Z, Chen J, Chen G. Zheng K, et al. Int J Mol Sci. 2024 Nov 2;25(21):11780. doi: 10.3390/ijms252111780. Int J Mol Sci. 2024. PMID: 39519332 Free PMC article. Review.
• Using human disease mutations to understand de novo DNA methyltransferase function.
  Rolls W, Wilson MD, Sproul D. Rolls W, et al. Biochem Soc Trans. 2024 Oct 30;52(5):2059-2075. doi: 10.1042/BST20231017. Biochem Soc Trans. 2024. PMID: 39446312 Free PMC article. Review.
• Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response.
  Tan L, Yin T, Xiang H, Wang L, Mudgal P, Chen J, Ding Y, Wang G, Lim BJW, Huang Y, Huang D, Liang Y, Alexander PB, Xiang K, Wang E, Yan C, Ma Z, Tan M, Li QJ, Wang XF. Tan L, et al. Nat Commun. 2024 Oct 3;15(1):8569. doi: 10.1038/s41467-024-52902-5. Nat Commun. 2024. PMID: 39362877 Free PMC article.
• DNA-binding proteins from MBD through ZF to BEN: recognition of cytosine methylation status by one arginine with two conformations.
  Zhang X, Blumenthal RM, Cheng X. Zhang X, et al. Nucleic Acids Res. 2024 Oct 28;52(19):11442-11454. doi: 10.1093/nar/gkae832. Nucleic Acids Res. 2024. PMID: 39329271 Free PMC article.
• STUB1-mediated K63-linked ubiquitination of UHRF1 promotes the progression of cholangiocarcinoma by maintaining DNA hypermethylation of PLA2G2A.
  Chen J, Wang D, Wu G, Xiong F, Liu W, Wang Q, Kuai Y, Huang W, Qi Y, Wang B, Chen Y. Chen J, et al. J Exp Clin Cancer Res. 2024 Sep 13;43(1):260. doi: 10.1186/s13046-024-03186-6. J Exp Clin Cancer Res. 2024. PMID: 39267107 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Nature Publishing Group
  • Ovid Technologies, Inc.

• Other Literature Sources

  • H1 Connect
  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • BioCyc
  • Gene Ontology
  • GlyGen glycoinformatics resource
  • Mouse Genome Informatics (MGI)