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This Week in PNAS: Jun 9, 2009

Scientists at the the University of Texas Southwestern Medical Center and Chinese Academy of Sciences in Beijing collaborated on a study published this week in the early online edition of PNAS that looked at phosphorylation events of the Neurospora core circadian protein FRQ. Using mass spec, they identified 43 FRQ phosphorylation sites in vivo and another 33 by in vitro kinase assays. "Whole-cell metabolic isotope labeling and quantitative MS analyses suggest that circadian oscillation of the FRQ phosphorylation profile is primarily due to progressive phosphorylation at the majority of these newly discovered phosphorylation sites," they write in the abstract, suggesting that FRQ stability and thus, circadian rhythm, is mediated by phosphorylation.

Work by Yann Gambina and Alexander Schug at Scripps and UCSD, respectively, used single-molecule fluorescence resonance energy transfer (smFRET) measurements to see that two "symmetrically opposed conformations" for a mutant of the Rop-homodimer (Repressor of Primer) exist together. Mild denaturing conditions can affect the sensitive balance between the conformations, they found, and that the proteins can switch between conformations.

More proteomics work on structure/function relationship revealed that the physicochemical properties of proteins' amino acid sequences can affect the way they associate and interact. Upon analyzing all the protein-protein complexes in the Protein Data Bank, scientists in the UK found that interface regions are more likely to aggregate than other surface regions. This suggests that interactions that promote function, like hydrophobic and electrostatic forces, can also cause abnormal associations. Further work showed that disulfide bonds and salt bridges, however, can act as stabilizing forces.

Senior author Gareth Bond at Oxford's Ludwig Institute for Cancer Research led work that studied the effect of mutations in the MDM4 gene, a homolog of the mouse double minute 2 (MDM2) oncogene, which binds to and inhibits p53. Looking at the haplotype structure of MDM4 in multiple populations and association studies in five different patient populations, they found that SNPs in this region lend an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively, they say.

The Scan

Study Finds Few FDA Post-Market Regulatory Actions Backed by Research, Public Assessments

A Yale University-led team examines in The BMJ safety signals from the US FDA Adverse Event Reporting System and whether they led to regulatory action.

Duke University Team Develops Programmable RNA Tool for Cell Editing

Researchers have developed an RNA-based editing tool that can target specific cells, as they describe in Nature.

Novel Gene Editing Approach for Treating Cystic Fibrosis

Researchers in Science Advances report on their development of a non-nuclease-based gene editing approach they hope to apply to treat cystic fibrosis.

Study Tracks Responses in Patients Pursuing Polygenic Risk Score Profiling

Using interviews, researchers in the European Journal of Human Genetics qualitatively assess individuals' motivations for, and experiences with, direct-to-consumer polygenic risk score testing.