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Scientists Crack A Key Enzyme Linked to Understand DNA Methylation from Scratch
SHIRLEY, NY, UNITED STATES - May 23, 2018 - Summary: A team at the University of California, Riverside, analyzed the crystal structure of an enzyme that plays a key role in DNA methylation, which found to be of great importance for understanding "DNA methylation from scratch."
A team at the University of California, Riverside, analyzed the crystal structure of an enzyme that plays a key role in DNA methylation, which is of great importance for understanding "DNA methylation from scratch."
The research was published in Nature. It was completed by Jikui Song of University and Gang Greg Wang of California Riverside.
DNA methylation alters gene expression. This basic cellular mechanism of action is important for the evolution of plants, animals and humans. Previous studies have found that DNA methylation can regulate genomic stability and cell differentiation.
In humans, errors in methylation are associated with various diseases, including cancer. In mammals, DNA methylation is initially established by two related enzymes: DNMT3A and DNMT3B during germ cell development and early embryonic development. Understanding how DNA methylation "starts from scratch" is difficult, and one of the challenges is to resolve the structure of these enzymes.
In this article, researchers at the University of California, Riverside, obtained the crystal structure of DNMT3A combined with a substrate. This breakthrough reveals important information about how this enzyme recognizes and methylates its substrate.
"This structure reveals how DNMT3A molecules target two adjacent substrate sites on the same DNA molecule. Our work presents the first structural point of view for de novo DNA methylation and to understand how DNMT3A mutations influence cancers, such as acute myelogenous leukemia. It provides models that provide important insights into the function of DNMT3B, Dr. Song said.
Understanding the structure of DNMT3A can help scientists regulate DNA methylation levels, gene expression, and cell differentiation, all of which are associated with diseases.
"This is particularly important for the long-term treatment of cancer."
At the same time, this study also explained why DNA methylation in mammals mainly occurs in "CpG dinucleotides."
"Scientists have no idea why the DNA methylation of mammals mainly occurs at the CpG site. Our understanding of the nascent DNA methylation was purely based on computer simulations and cannot reliably explain how DNMT3A works. How DNMT3A successfully binds to its substrate is also unknown. Our study has solved the DNMT3A-DNA complex structure, solved all these problems and provided new insights into how to generate specific DNA methylation patterns."
Due to the difficulty in producing stable enzyme-substrate complexes, studies of DNMT3A structures and substrates have been difficult.
In order to overcome this challenge, these researchers successfully developed a method to capture the reaction intermediates of DNMT3A-substrate complexes and resolved the structure by X-ray crystallography.
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