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Archive - Feb 3, 2017

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How Ribosomal Protein L4 Is Protected by Chaperone

For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes -- components of the cell that produce proteins -- has its own chaperone to guide it to the right place at the right time and protect it from harm. In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone. "Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter," says Dr. André Hoelz, Professor of Chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar." What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped." Dr. Hoelz is the principal investigator behind the study published online on February 2, 2017, in the Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly. In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.

Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras

Cancer is a heterogeneous disease, with myriad distinct subtypes that differ in their genetic roots. As a result, cancers rely on varied pathways for survival--and respond differently to anticancer agents. The challenge for researchers is to precisely define those diverse pathways and pinpoint vulnerabilities that may serve as drug targets for new anti-cancer treatments. Investigators at the Whitehead Institute and the Broad Institute have taken an important step in tackling that challenge: They have succeeded in identifying the set of essential genes--those required for cellular proliferation and survival--in each of 14 human acute myeloid leukemia (AML) cell lines that had previously been characterized by genome sequencing. By combining their "gene essentiality map" with the existing genomic information, their study revealed liabilities in genetically defined subset of cancers that could be exploited for new therapies. The report on their work, appearing in the online edition of Cell on February 2, 2017, is entitled “Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras.” A major aspect of the study focuses on the genes and protein pathways connected to the Ras oncogene, the most commonly mutated oncogene in human cancers which plays a role in AML, as well as many other cancers. "For the most part, the mutant Ras protein itself has been considered to be 'undruggable,’" explain Tim Wang, the paper's first author and an MIT graduate student researcher at Whitehead Institute and the Broad Institute. "An alternative approach has been to find other genes that Ras-mutant cancers rely on with the hope that one of them may be druggable.