MDC1 is a mediator of the mammalian DNA damage checkpoint

To counteract the continuous exposure of cells to agents that damage DNA, cells have evolved complex regulatory networks called checkpoints to sense DNA damage and coordinate DNA replication, cell-cycle arrest and DNA repair. It has recently been shown that the histone H2A variant H2AX specifically controls the recruitment of DNA repair proteins to the sites of DNA damage. Here we identify a novel BRCA1 carboxy-terminal (BRCT) and forkhead-associated (FHA) domain-containing protein, MDC1 (mediator of DNA damage checkpoint protein 1), which works with H2AX to promote recruitment of repair proteins to the sites of DNA breaks and which, in addition, controls damage-induced cell-cycle arrest checkpoints. MDC1 forms foci that co-localize extensively with gamma-H2AX foci within minutes after exposure to ionizing radiation. H2AX is required for MDC1 foci formation, and MDC1 forms complexes with phosphorylated H2AX. Furthermore, this interaction is phosphorylation dependent as peptides containing the phosphorylated site on H2AX bind MDC1 in a phosphorylation-dependent manner. We have shown by using small interfering RNA (siRNA) that cells lacking MDC1 are sensitive to ionizing radiation, and that MDC1 controls the formation of damage-induced 53BP1, BRCA1 and MRN foci, in part by promoting efficient H2AX phosphorylation. In addition, cells lacking MDC1 also fail to activate the intra-S phase and G2/M phase cell-cycle checkpoints properly after exposure to ionizing radiation, which was associated with an inability to regulate Chk1 properly. These results highlight a crucial role for MDC1 in mediating transduction of the DNA damage signal.     

Gnawing activity,dietary carbohydrate deficiency and oothecal production in the American cockroach (Periplaneta americana)

Summary The gnawing activity of adult female cockroaches was assessed by the dry weight loss of cotton fibre supplied to individual insects. In animals maintained on a carbohydrate-deficient diet the use of fibre was significantly less than in animals receiving a balanced diet. A comparison with controls showed that under both dietary regimes access to a fibre source did not significantly increase the mean, total number of oothecae produced.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer

We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.     

Lung cancer: intragenic ERBB2 kinase mutations in tumours

The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.     

Seismic considerations for spent nuclear fuel storage in dry casks

o aid the United States’ Nuclear Regulatory Commission, Sandia National Laboratories (SNL) was contracted to investigate the seismic behavior of typical dry cask storage systems. Parametric evaluations characterized the sensitivity of calculated cask response characteristics to input parameters. The parametric evaluation investigated two generic cask design (cylindrical and rectangular), three different foundation types (soft soil, hard soil, and rock), and three different cask to pad coefficients of friction (0.2, 0.55, 0.8) for earthquakes with peak ground accelerations of 0.25g, 0.6g, 1.0g and 1.25g. A total of 1 165 analyses were completed, with regression analyses being performed on the resulting cask response data to determine relationships relating the mean (and 16 % and 84 % confidence intervals on the mean) to peak ground acceleration, peak ground velocity, and pseudo-spectral acceleration at 1 Hz and 5 % damping. In general, the cylindrical casks experienced significantly larger responses in comparison to the rectangular cask. The cylindrical cask experienced larger top of cask displacements, larger cask rotations (rocking), and more occurrences of cask toppling (the rectangular cask never toppled over). The cylindrical cask was also susceptible to rolling once rocking had been initiated, a behavior not observed in the rectangular cask. Cask response was not overly sensitive to foundation type, but was significantly dependent on the response spectrum employed.