Methodological approaches in application of synthetic lethality screening towards anticancer therapy

A promising direction in the development of selective less toxic cancer drugs is the usage of synthetic lethality concept. The availability of large-scale synthetic low-molecular-weight chemical libraries has allowed HTS for compounds synergistic lethal with defined human cancer aberrations in activated oncogenes or tumour suppressor genes. The search for synthetic lethal chemicals in human/mouse tumour cells is greatly aided by a prior knowledge of relevant signalling and DNA repair pathways, allowing for educated guesses on the preferred potential therapeutic targets. The recent generation of human/rodents genome-wide siRNAs, and shRNA-expressing libraries, should further advance this more focused approach to cancer drug discovery

The (4;11)(q21;q23) chromosome translocations in acute leukemias involve the VDJ recombinase.

Chromosomal region 11q23 is frequently rearranged in acute lymphocytic leukemias (ALLs) and in acute myeloid leukemias (AMLs), mostly in reciprocal exchanges with various translocation partners. The most common of these translocations is t(4;11)(q21;q23). It is present in approximately 10% of ALL patients, most frequently in very young children. We have recently cloned a region of chromosome 11, the ALL-1 locus, found to be rearranged in malignant cells from patients with the t(4;11), t(9;11), t(11;19), t(1;11), t(6;11), t(10;11), and del(11q23) chromosomal abnormalities. Here we report the cloning and characterization of chromosomal breakpoints from leukemic cells with t(4;11) aberrations. The breakpoints cluster in regions of 7-8 kilobases on both chromosomes 4 and 11. The presence of heptamer- and nonamer-like sequences at the sites of breakage suggests that the VDJ recombinase utilized for immunoglobulin gene rearrangement is also directly involved in these translocations. We also show that leukemic cells with t(4;11) express altered RNAs transcribed from the derivative chromosomes 11 and 4

Fluorescence as a tool to understand changes in photosynthetic electron flow regulation

International audienceThe physiological state of a chloroplast is stronglyinfluenced by both biotic and abiotic conditions.Unfavourable growth conditions lead to photosyntheticstress. Chlorophyll a fluorescence is a widelyused probe of photosynthetic activity (specificallyPSII), and therefore stress which specifically targetsthe electron transport pathway and associated alternativeelectron cycling pathways. By manipulating theprocesses that control photosynthesis, affecting thechlorophyll a fluorescence, yields detailed insight intothe biochemicalpathways. Light that is captured by achlorophyll molecule can be utilised in three competingprocesses; electron transport, energy dissipation(via heat) and chlorophyll a fluorescence emission.Electrons produced by water-splitting are not alwaysused in carbon fixation; if the incident irradiancegeneratesmore electrons than the dark reactionscan use in carbon fixation, damage will occur to the photosynthetic apparatus. If carbon fixation is inhibitedby temperature or reduced inorganic carbon (Ci), ATPor NADPH availability, then the photosystem dynamicallyadjusts and uses alternate sinks for electrons, suchas molecular oxygen (water-water cycle or Mehler ascorbateperoxidase reaction). The process of stress acclimationleads to a number of photoprotective pathwaysand we describe how inhibitors can be used to identifythese particular processes. In this chapter, we describethe processes controlling electron transport as influencedby light-induced stress