Structure-Based Mechanistic Insights into DNMT1-Mediated Maintenance DNA Methylation

Journal Article · Mon Mar 26 04:00:00 EDT 2012 · Science

DOI:https://doi.org/10.1126/science.1214453· OSTI ID:1035701

Song, Jikui; Teplova, Marianna; Ishibe-Murakami, Satoko; Patel, Dinshaw J ^[1]

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1. MSKCC

DNMT1, the major maintenance DNA methyltransferase in animals, helps to regulate gene expression, genome imprinting, and X-chromosome inactivation. We report on the crystal structure of a productive covalent mouse DNMT1(731-1602)-DNA complex containing a central hemimethylated CpG site. The methyl group of methylcytosine is positioned within a shallow hydrophobic concave surface, whereas the cytosine on the target strand is looped out and covalently anchored within the catalytic pocket. The DNA is distorted at the hemimethylated CpG step, with side chains from catalytic and recognition loops inserting through both grooves to fill an intercalation-type cavity associated with a dual base flip-out on partner strands. Structural and biochemical data establish how a combination of active and autoinhibitory mechanisms ensures the high fidelity of DNMT1-mediated maintenance DNA methylation.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: OTHER
• OSTI ID: 1035701
• Journal Information: Science, Journal Name: Science Journal Issue: 02, 2012 Vol. 335; ISSN SCIEAS; ISSN 0036-8075
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ANIMALS
CHAINS
CRYSTAL STRUCTURE
CYTOSINE
DNA
GENES
INACTIVATION
MAINTENANCE
METHYLATION
TARGETS
X CHROMOSOME