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Archive - Sep 2, 2018

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Breakthrough in Understanding Warsaw Breakage Syndrome and Function of Key DNA Repair Enzyme DDX11 Helicase

Researchers from Tokyo Metropolitan University and the FIRC Institute of Molecular Oncology (IFOM) in Italy have uncovered a previously unknown function of the DDX11 helicase enzyme. Mutations in the gene which codes for DDX11 are known to be implicated in Warsaw breakage syndrome. The scientists showed that DDX11 plays an important role in DNA repair, and functions as a backup to the Fanconi anemia (FA) pathway, whose malfunction is associated with another life-debilitating condition. DNA plays a central role in the biological function of the cell, but it is constantly being damaged, both spontaneously and through environmental factors. Failure to successfully repair these lesions can lead to malignant tumors. Understanding how damaged DNA is repaired is of the utmost importance; in fact, pioneering work on the subject was recognized with the 2015 Nobel Prize for Chemistry (https://www.nobelprize.org/prizes/chemistry/2015/summary/). The new work was published online on August 14, 2018 in PNAS. The open-access article is titled “Warsaw Breakage Syndrome DDX11 Helicase Acts Jointly with RAD17 in the Repair of Bulky Lesions and Replication Through Abasic Sites.” Warsaw breakage syndrome (WABS) is a genetic disorder; afflicted individuals suffer from mild to severe intellectual disability and growth impairment amongst other potential abnormalities. It was known that mutations in the DDX11 gene in chromosome 12 in the human genome and the enzyme it codes for, the DDX11 helicase, were responsible for the onset of WABS, yet the mechanism by which DDX11 acted remained unclear. Thus, a collaboration led by Dr. Dana Branzei of IFOM, Italy, and Professor Kouji Hirota of Tokyo Metropolitan University set out to investigate the role played by DDX11 using avian cells, particularly noting similarities in the cells of WABS patients to those of Fanconi anemia (FA).

Altered Timing in Growth Signaling May Be Key in Many Cancers; Novel Optogenetics Approach Reveals Importance of Precise Timing in Cellular Signaling Circuits

Genetic mutations in a form of non-small cell lung cancer (NSCLC) may drive tumor formation by blurring cells' perception of key growth signals, according to a new laboratory study published online on August 29, 2018 in Science. The article is titled “Cancer Mutations and Targeted Drugs Can Disrupt Dynamic Signal Encoding by the Ras-Erk Pathway.” The research, led by UC San Francisco (UCSF) researchers, could have important implications for understanding and ultimately targeting the defective mechanisms underlying many human cancers. Healthy cells rely on the central Ras/Erk growth signaling pathway (also known as the Ras/MAPK pathway) to interpret external cues about how and when to grow, divide, and migrate, but defects in how these messages are communicated can cause cells to grow out of control and aggressively invade other parts of the body. Such mutations are found in the majority of human cancers, making treatments for Ras/Erk defects a "holy grail" of cancer research. Decades of study have led scientists to believe that Ras/Erk-driven cancers occur when mutations cause one or more components of the pathway to get stuck in a pro-growth state. Researchers have labored to develop targeted treatments that flip these broken switches back off, but so far most have failed to make it through clinical trials. Now, using a high-throughput technique developed at UCSF that allows scientists to take control of Ras/Erk signaling using pulses of light, and then quickly read out resulting genomic activity, researchers have made a surprising discovery about this extensively studied pathway.