Breaking News
July 19, 2018 - Refining standards of maternal-fetal care
July 19, 2018 - Stitching single cells together any which way you want to
July 19, 2018 - Study identifies RNA molecules that regulate male hormones in prostate cancer
July 19, 2018 - New machine-learning model shows promise in predicting undiagnosed dementia
July 19, 2018 - Sleep supports antioxidant processes, study suggests
July 19, 2018 - MiRagen Therapeutics Announces Initiation of Phase 2 Clinical Trial of MRG-201
July 19, 2018 - Unique brain ‘fingerprint’ can predict drug effectiveness
July 19, 2018 - Life on the border: Struggling to survive in Jordan
July 19, 2018 - CT scans may raise brain tumor risk
July 19, 2018 - Moderate alcohol intake linked with improved male fertility
July 19, 2018 - Alcohol-related cirrhosis mortality on the rise among young adults
July 19, 2018 - Study uncovers new protein complex that shields broken DNA ends
July 19, 2018 - Regular sunscreen use protects young people from melanoma
July 19, 2018 - Using non-invasive brain recordings to characterize activity in deep structures
July 19, 2018 - Mediterranean diet could influence academic performance through effects on sleep quality
July 19, 2018 - Woman’s pregnancy history may be linked to Alzheimer’s disease risk
July 19, 2018 - Study calls for new gold standard in research to treat non-alcoholic steatohepatitis
July 19, 2018 - Cancer patients receiving anti-PD-1 therapies may experience delayed skin reactions
July 19, 2018 - Scientists study adverse effects of carbon, silicon nanotubes and carbon nanofibers
July 19, 2018 - Keck Hospital of USC receives Magnet recognition for excellence in nursing
July 19, 2018 - Scientists identify hidden signals in RNAs that control protein synthesis
July 19, 2018 - Quadrivalent HPV Vaccine Not Tied to Spontaneous Abortion
July 19, 2018 - FDA OKs first drug made to reduce excessive sweating
July 19, 2018 - New findings do no support caffeine as effective appetite suppressant or weight-loss aid
July 19, 2018 - Study evaluates Neoteryx’s VAMS technology for monitoring HbA1c levels of diabetic children
July 19, 2018 - New clinical trial examines use of adrenaline to treat cardiac arrests
July 19, 2018 - Early surgical intervention may improve outcomes for patients with mitral valve disease
July 19, 2018 - Prolonged preoperative opioid use linked to adverse outcomes after total knee and hip arthroplasty
July 19, 2018 - Biophysicists use infrared sensor as new method for drug discovery
July 19, 2018 - Rat study shows negative effects of perinatal exposure to phthalates
July 19, 2018 - Children with disabilities endure long waits for life-changing medical equipment
July 19, 2018 - Ways to stay safe while camping and hiking
July 19, 2018 - People with HIV twice as likely to suffer from heart disease
July 19, 2018 - On-the-Job Stress Relief – Drugs.com MedNews
July 19, 2018 - Compounds found in green tea and wine may block formation of toxic metabolites
July 19, 2018 - Gene regulator associated with protein pileup in exfoliation glaucoma
July 19, 2018 - Trump administration summons immigrant infants
July 19, 2018 - FDA grants approval for first breast cancer drug through ‘Real-Time Oncology Review’
July 19, 2018 - Five tips for men seeking plastic surgery
July 19, 2018 - Researchers discover the reasons why some people get dizzy when hearing certain sounds
July 19, 2018 - Research project investigates snake venom treatment as antibiotic alternative for eye infections
July 19, 2018 - Melanoma could soon be detected using a blood test
July 19, 2018 - Exposure to bright light may have big impact on sleep-related behavior in children
July 19, 2018 - Deleting single gene in gut bacteria affects metabolism, reduces weight gain in mice
July 19, 2018 - New proteomics studies help gain more insights into Alzheimer’s, cancer and listeriosis
July 19, 2018 - Study finds major discrepancies in prescription drug labeling pregnancy information across four countries
July 19, 2018 - Cellectar’s CLR 131 Receives FDA Orphan Drug Designation for Treatment of Ewing’s Sarcoma
July 19, 2018 - Watching the immune system in action reveals what happens when things goes wrong
July 19, 2018 - Increasing blood sugar levels improves memory and performance in older adults
July 19, 2018 - Connection between self-regulation and obesity appears to be different for girls and boys
July 19, 2018 - Researchers develop new, less destructive method for whitening teeth
July 19, 2018 - Revving up innate control of viral infection requires a three-cell ignition
July 19, 2018 - Inaccurate direct-to-consumer raw genetic data can harm patients, new research suggests
July 19, 2018 - Weight loss surgery is effective under the right situations
July 19, 2018 - BioTek awarded patent for autofocus feature on microplate reader
July 19, 2018 - Low-carb diets reduce stiffness of arteries in women and promote weight loss in men
July 19, 2018 - New review examines cannabinoids’ potential for direct treatment of cancer
July 19, 2018 - Allergic responses may help protect the skin against cancer, research suggests
July 19, 2018 - Inappropriate Prescribing of Abx High in Urgent Care Centers
July 19, 2018 - Many at risk for HIV despite lifesaving pill
July 19, 2018 - Tips for doctors and parents on the harms of marijuana use for teens
July 18, 2018 - Researchers detect presence of IgE antibodies after kidney transplantation
July 18, 2018 - New technique allows researchers to create large scale, personalized bone grafts
July 18, 2018 - Smoking May Boost Atrial Fibrillation Risk
July 18, 2018 - Genome editing method targets AIDS virus
July 18, 2018 - These things matter: Medical complications are not inevitable, a physician writes
July 18, 2018 - Cognitive functions often wilt as water departs the body, shows study
July 18, 2018 - Origins of bread found 14,400 years ago in Jordan
July 18, 2018 - Low-dose ketamine found to be as effective as opioids for treating acute pain
July 18, 2018 - Novel bioengineering technique could help repair bone defects
July 18, 2018 - Researchers identify new potential target protein for colon cancer
July 18, 2018 - Air pollution contributes significantly to diabetes globally
July 18, 2018 - Cell membrane’s importance offers new strategy to fight infections
July 18, 2018 - Researchers identify key protein involved in irregular brain cell activity
July 18, 2018 - 3D modeling of drug resistance could lead to more effective cancer treatment
July 18, 2018 - Hunger hormones could be key to new treatments for drug, alcohol addiction
July 18, 2018 - Nitrate-cured meats may contribute to mania, study finds
July 18, 2018 - Why men may recover more quickly from influenza infections than women
July 18, 2018 - Study finds discharge against medical advice as predictor of readmissions in heart attack patients
July 18, 2018 - KemPharm Announces Top Line Results from KP415.E01 Efficacy and Safety Trial in Children With ADHD
Scientists crack structure of enzyme complex linked to cancer

Scientists crack structure of enzyme complex linked to cancer

image_pdfDownload PDFimage_print
Image shows the DNMT3A-DNA complex. A research team led by Jikui Song cracked the crystal structure for DNMT3A-DNA complex. The structure reveals that DNMT3A molecules attack two substrate sites adjacent to each other on the same DNA molecule. DNMT3L (green) is a regulatory protein of DNMT3A. Bp (base pairs) is a unit of length, with one bp corresponding to approximately 3.4 Å of length along the DNA (brown) strand. Credit: Song lab, UC Riverside.

A research team led by a biochemist at the University of California, Riverside has solved the crystal structure for an enzyme that plays a key role in DNA methylation, the process by which methyl groups are added to the DNA molecule.

DNA methylation alters gene expression. This fundamental cellular mechanism critically influences plant, animal, and human development. It is known to regulate genome stability and cell differentiation. In humans, errors in methylation have been associated with various diseases, including cancer.

In mammals, DNA methylation is established de novo (afresh) by closely related enzymes, DNMT3A and DNMT3B, during germ cell development and early embryonic development. One difficulty in understanding how de novo DNA methylation works is that the structures of these enzymes are not known.

The UC Riverside-led team has now solved the crystal structure for substrate-bound DNMT3A. This breakthrough reveals how the enzyme recognizes and methylates its substrates—important information for understanding de novo DNA methlylation. A substrate is a material or substance on which an enzyme acts.

“The structure reveals that DNMT3A molecules attack two substrate sites adjacent to each other on the same DNA molecule,” said Jikui Song, an associate professor of biochemistry who led the research project. “This now offers us a much clearer view on how de novo DNA methylation takes place. Our work presents the first structural view of de novo DNA methylation and presents a model for how some DNMT3A mutations contribute to cancers, such as acute myeloid leukemia. This study should provide important insights into the function of DNMT3B as well.”

Song explained the structural knowledge of DNMT3A will allow scientists to control DNA methylation content, gene expression, and cell differentiation—all of which are linked to diseases and finding cures for them.

“It especially has important implications in cancer therapy in the long term,” he said.

Study results appear today in Nature.

The DNMT3A structure that Song’s team cracked explains why mammalian DNA methylation predominantly occurs at “CpG dinucleotides”—DNA locations where cytosine nucleotides are next to guanidine nucleotides.

“Before our study, why mammalian DNA methylation mostly occurs at the CpG sites was not understood, and our understanding of de novo DNA methylation was purely based on computational modeling, which cannot reliably explain how DNMT3A works,” Song said. “Just how DNMT3A succeeded in binding to its substrate was not understood either. Our structure for DNMT3A-DNA complex addresses all these concerns, offering a far better understanding of how specific DNA methylation patterns are generated.”

The study of DNMT3A structure with substrates has long been hindered by the difficulty in producing a stable enzyme-substrate complex.

“To overcome this challenge, we successfully developed a method to trap the reaction intermediate of DNMT3A-substrate complex, and solved the structure by X-ray crystallography,” Song said.

He was joined in the study by Zhi-Min Zhang (first author of the research paper), Pengcheng Wang, Yang Yu, Linfeng Gao, Shuo Liu, Debin Ji, and Yinsheng Wang at UCR; and Rui Lu, Dong-Liang Chen, Scott B Rothbart, and co-leader Gang Greg Wang at the University of North Carolina at Chapel Hill. The Song group solved the crystal structure. The Wang group performed genomic DNA methylation analysis.


Explore further:
Important mechanism of epigenetic gene regulation identified

More information:
Zhi-Min Zhang et al, Structural basis for DNMT3A-mediated de novo DNA methylation, Nature (2018). DOI: 10.1038/nature25477

Journal reference:
Nature

Provided by:
University of California – Riverside

Tagged with:

About author

Related Articles