Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes

Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD⁺-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development. We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone modifications associated with constitutive heterochromatin integrity.     

A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1

We performed a genome-wide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease and 368 controls. A total of 7,159 of these SNPs were informative. We followed up on all 72 SNPs with P 0.4), these data suggest that the underlying biological process may be specific to Crohn disease.     

Genetic basis of individual differences in the response to small-molecule drugs in yeast

Individual response to small-molecule drugs is variable; a drug that provides a cure for some may confer no therapeutic benefit or trigger an adverse reaction in others. To begin to understand such differences systematically, we treated 104 genotyped segregants from a cross between two yeast strains with a collection of 100 diverse small molecules. We used linkage analysis to identify 124 distinct linkages between genetic markers and response to 83 compounds. The linked markers clustered at eight genomic locations, or quantitative-trait locus 'hotspots', that contain one or more polymorphisms that affect response to multiple small molecules. We also experimentally verified that a deficiency in leucine biosynthesis caused by a deletion of LEU2 underlies sensitivity to niguldipine, which is structurally related to therapeutic calcium channel blockers, and that a natural coding-region polymorphism in the inorganic phosphate transporter PHO84 underlies sensitivity to two polychlorinated phenols that uncouple oxidative phosphorylation. Our results provide a step toward a systematic understanding of small-molecule drug action in genetically distinct individuals.     

A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease

With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.     

Synthese der Spiroaminoketal-Gruppierung von Solanum-Alkaloiden

Summary The ring-E opened dihydro derivatives of tomatidine and soladulcidine give the corresponding N-chloroamines with N-chlorosuccinimide. Treatment of these compounds with sodium methoxide yields the spiroaminoketal alkaloids, tomatidine and soladulcidine respectively, in high yields, probably via instable C=N-unsaturated intermediates which undergo spontaneous stereospecific cyclisation.

---

---

Solanum-Alkaloide. XIII. Mitteilung. XII. Mitteilung:K. Schreiber undH. Ripperger, Exper.16, 536 (1960).     

Multiple tumour-specific antigens expressed on a single tumour cell

Tumours induced by physical or chemical carcinogens often express tumour-specific antigens that can induce strong protective immune defence in the host. The diversity of these unique antigens among different tumours is seemingly endless, and has been compared to that of immune receptors. At present, the nature and complexity of this antigenicity is not known for any single tumour. Here we describe the unique antigenicity expressed by a murine ultraviolet light (UV)-induced fibrosarcoma. This tumour is clearly subject to immune surveillance by the normal host, and does not grow progressively unless it undergoes antigenic changes. Using defined monoclonal T-cell probes and tumour variants selected in vitro with these probes, we found that the total antigenicity consisted of multiple independent components, all of which were tumour-specific and expressed simultaneously on the same tumour cell. The demonstration of this antigenic complexity will enable us to identify and compare the molecular composition of the components of this antigen, as well as to determine their individual roles in tumour rejection and escape.