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Archive - Dec 28, 2013

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International Team Completes Systematic, Genomic Study of Cervical Cancer

Researchers from the Boston area, Mexico, and Norway have completed a comprehensive genomic analysis of cervical cancer in two patient populations. The study identified recurrent genetic mutations not previously found in cervical cancer, including at least one for which targeted treatments have been approved for other forms of cancer. The findings also shed light on the role human papillomavirus (HPV) plays in the development of cervical cancer. The study, which appeared online on December 25, 2013 in Nature, addresses a public health concern of global significance: cervical cancer is the second most common cancer in women and is responsible for approximately 10 percent of cancer deaths in women – particularly in developing countries where screening methods are not readily accessible. Almost all cases of the disease are caused by exposure to HPV and it is expected that vaccination efforts targeting HPV will decrease cervical cancer cases over time. In the meantime, however, the disease remains a significant threat to women's health. "Cancer is a disease that affects the whole world, and one question that always arises is: is a given cancer type similar or different across populations?" explained Dr. Matthew Meyerson, one of the paper's co-senior authors. Dr. Meyerson is a professor of pathology and medical oncology at Dana-Farber Cancer Institute and a senior associate member of the Broad Institute.

Epigenetics Mystery Solved: Structure of Tet Enzyme Family Member Complexed with DNA Is Detemined

Scientists have obtained the first detailed molecular structure of a member of the Tet family of enzymes. The finding is important for the field of epigenetics because Tet enzymes chemically modify DNA, changing signposts that tell the cell's machinery "this gene is shut off" into other signs that say "ready for a change." Tet enzymes' roles have come to light only in the last five years; they are needed for stem cells to maintain their multipotent state, and are involved in early embryonic and brain development and in cancer. The results, which could help scientists understand how Tet enzymes are regulated and look for drugs that manipulate them, were published online on December 25, 2013 in Nature. Researchers led by Xiaodong Cheng, Ph.D., determined the structure of a Tet family member from Naegleria gruberi by X-ray crystallography. The structure shows how the enzyme interacts with its target DNA (see image courtesy of Dr. Xiaodong Cheng, Emory University), bending the double helix and flipping out the base that is to be modified. "This base flipping mechanism is also used by other enzymes that modify and repair DNA, but we can see from the structure that the Tet family enzymes interact with the DNA in a distinct way," Dr. Cheng says. Dr. Cheng is professor of biochemistry at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar. The first author of the paper is research associate Hideharu Hashimoto, Ph.D. A team led by Yu Zheng, Ph.D., a senior research scientist at New England Biolabs, contributed to the paper by analyzing the enzymatic activity of Tet using liquid chromatography–mass spectrometry. Using oxygen, Tet enzymes change 5-methylcytosine into 5-hydroxymethylcytosine and other oxidized forms of methylcytosine.

Long Intergenic Noncoding RNA Associated with Kawasaki Disease

Sanford-Burnham Medical Research Institute scientists have discovered a new molecule that forms when certain white blood cells—macrophages—are stimulated in response to pathogens. The molecule, termed "THRIL," helps regulate the immune response and shows an association with Kawasaki disease. The findings suggest that THRIL may contribute to other inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. The study, published online on December 26, 2013 in PNAS, measured large intergenic noncoding RNA (lincRNA) produced when the immune system is activated. One lincRNA was found to bind heterogenous nuclear ribonucleoprotein L (hnRNPL), creating a new molecule that regulates genetic control of TNF-alpha—a potent cytokine that promotes inflammation. The authors named the molecule THRIL, after TNF-alpha and hnRNPL-related immunoregulatory lincRNA. Large noncoding RNA corresponds to the parts of the genome that do not code for protein. "For some time we have known that noncoding regions of RNA play important roles in regulating the immune response to microbial pathogens," said Tariq Rana, Ph.D., senior author of the study and professor in the Sanford Children's Health Research Center and director of the RNA Biology Program at Sanford-Burnham. "When we realized that THRIL functioned to control the TNF-alpha gene, we wanted to see if it mirrors the progression in inflammatory diseases." Collaborating with Jane Burns, M.D., professor of pediatrics at Rady Children's Hospital and the University of California-San Diego (UC San Diego), Dr. Rana's team measured THRIL levels in Kawasaki disease samples at different stages of the disease, and found that levels were at their lowest during the acute stage of the disease—when TNF-alpha levels are at their highest.