Identification and dissection of a complex DNA repair sensitivity phenotype in Baker's yeast

Complex traits typically involve the contribution of multiple gene variants. In this study, we took advantage of a high-density genotyping analysis of the BY (S288c) and RM strains of Saccharomyces cerevisiae and of 123 derived spore progeny to identify the genetic loci that underlie a complex DNA repair sensitivity phenotype. This was accomplished by screening hybrid yeast progeny for sensitivity to a variety of DNA damaging agents. Both the BY and RM strains are resistant to the ultraviolet light–mimetic agent 4-nitroquinoline 1-oxide (4-NQO); however, hybrid progeny from a BY×RM cross displayed varying sensitivities to the drug. We mapped a major quantitative trait locus (QTL), RAD5, and identified the exact polymorphism within this locus responsible for 4-NQO sensitivity. By using a backcrossing strategy along with array-assisted bulk segregant analysis, we identified one other locus, MKT1, and a QTL on Chromosome VII that also link to the hybrid 4-NQO–sensitive phenotype but confer more minor effects. This work suggests an additive model for sensitivity to 4-NQO and provides a strategy for mapping both major and minor QTL that confer background-specific phenotypes. It also provides tools for understanding the effect of genetic background on sensitivity to genotoxic agents.     

Focusing the view on nature's water-splitting catalyst

Nature invented a catalyst about 3Gyr ago, which splits water with high efficiency into molecular oxygen and hydrogen equivalents (protons and electrons). This reaction is energetically driven by sunlight and the active centre contains relatively cheap and abundant metals: manganese and calcium. This biological system therefore forms the paradigm for all man-made attempts for direct solar fuel production, and several studies are underway to determine the electronic and geometric structures of this catalyst. In this report we briefly summarize the problems and the current status of these efforts and propose a density functional theory-based strategy for obtaining a reliable high-resolution structure of this unique catalyst that includes both the inorganic core and the first ligand sphere.     

Sialylation in protostomes: a perspective from <Emphasis Type="Italic">Drosophila</Emphasis> genetics and biochemistry

Numerous studies have revealed important functions for sialylation in both prokaryotes and higher animals. However, the genetic and biochemical potential for sialylation in Drosophila has only been confirmed recently. Recent studies suggest significant similarities between the sialylation pathways of vertebrates and insects and provide evidence for their common evolutionary origin. These new data support the hypothesis that sialylation in insects is a specialized and developmentally regulated process which likely plays a prominent role in the nervous system. Yet several key issues remain to be addressed in Drosophila, including the initiation of sialic acid de novo biosynthesis and understanding the structure and function of sialylated glycoconjugates. This review discusses our current knowledge of the Drosophila sialylation pathway, as compared to the pathway in bacteria and vertebrates. We arrive at the conclusion that Drosophila is emerging as a useful model organism that is poised to shed new light on the function of sialylation not only in protostomes, but also in a larger evolutionary context. K. Koles and E. Repnikova contributed equally to this work.     

Semi-rigid tripeptide agonists of melanocortin receptors

A series of 30 RCO–HfR–NH₂ derivatives show preference for the mouse MC1R vs MC3-5Rs. trans-4-HOC₆H₄CHCHCO–HfR–NH₂ (13) [EC₅₀ (nM): MC1R 83, MC3R 20500, MC4R 18130 and MC5R 935; ratio 1:246:217:11] is 11 times more potent than the lead compound LK-394 Ph(CH₂)₃CO–HfR–NH₂ (2) and only 11 times less potent than the native tridecapeptide α-MSH at mMC1R. Differences in conformations of 2 and 13 are discussed.