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

By J. Sharif, M. Muto, S. Takebayashi, I. Suetake, A. Iwamatsu, T. Endo, J. Shinga, Y. Mizutani-Koseki, Tetsuro Toyoda, K. Okamura and 4 more. Nature, 2007

1,314 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9a5fe57048507499890ce6bab7a2c06b62892966

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Citations in the corpus

• DNA methylation: superior or subordinate in the epigenetic hierarchy? (2011, background): “UHRF1 preferentially binds to hemimethylated DNA, interacts with DNMT1, and is required for DNMT1 localization to replicating heterochromatic regions.(41,42) In addition, UHRF1 specifically interacts with peptides that are methylated at H3K9 in vitro,(12,43) and it resides in a complex with HDACs an”
• Linking DNA methylation and histone modification: patterns and paradigms (2009, background): “Recent studies indicate that DNMT1, together with the E3 ubiquitin-protein ligase UHRF1 (also known as Np95 or ICBP90), specifically recognizes the methylated CpG residues of the hemimethylated DNA that is generated during DNA replication and methylates the opposite stran”
• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “The pattern of DNA methylation is then faithfully maintained during DNA replication by the maintenance methyltransferase Dnmt1, which is recruited to replication foci via its physical interaction with the ubiquitin-like plant homeodomain and RING finger domain 1 (Uhrf1) that strongly binds to hemime”
• The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells (2012, background): “Uhrf1), which targets Dnmt1 to the DNA replication machinery to maintain methylation during mitosis (Bostick et al., 2007; Sharif et al., 2007), are downregulated in early PGCs (Kurimoto et al.”
• Interpreting thelanguage of histone and DNA modifications (2014, background): “Indeed, deletion of Np95 (mouse UHRF1) results in a pronounced reduction in cellular DNA methylation levels [159,160], and the SRA interaction with DNA is required for DNMT1 chromatin targeting and subsequent DNA methylation maintenance [161].”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “During mitosis, the global CpG methylation pattern is faithfully maintained in daughter cells through the action of maintenance DNA methyltransferase DNMT1 and its obligate partner, the ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1), which preferentially recognizes hemimethylated ”
• Chromatin Structure and the Inheritance of Epigenetic Information (2010, background): “One explanation for this observation came from recent reports of another protein, nuclear protein 95 (NP95, also known as UHRF1 ), that interacts with DNMT1 and PCN”
• Conservation and divergence of methylation patterning in plants and animals (2010, background): “Uhrf1 acts in part by directly recognizing hemimethylated DNA that is produced after DNA replication, likely facilitating Dnmt1 activity at these sites (27, 28, 31).”