53BP1 facilitates long-range DNA end-joining during V(D)J recombination

Variable, diversity and joining (V(D)J) recombination and class-switch recombination use overlapping but distinct non-homologous end joining pathways to repair DNA double-strand-break intermediates. 53BP1 is a DNA-damage-response protein that is rapidly recruited to sites of chromosomal double-strand breaks, where it seems to function in a subset of ataxia telangiectasia mutated (ATM) kinase-, H2A histone family member X (H2AX, also known as H2AFX)- and mediator of DNA damage checkpoint 1 (MDC1)-dependent events. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination. Here we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1-deficient lymphocytes that is distinct from that found in classical non-homologous-end-joining-, H2ax-, Mdc1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of unrepaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes that have antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks.     

Adhesion and aggregation of human platelets to rabbit subendothelium. A new approach for investigation: specific antibodies

An SgG antibody occurring in a recently transfused thrombasthenic patient inhibited all the ADP-mediated aggregations and platelet-platelet interaction (thrombus formation) on rabbit aorta subendothelium; another IgG antibody occurring in a multitransfused Bernard-Soulier patient inhibited ristocetin and bovine factor VIII mediated aggregation and platelet-subendothelium interaction.     

Colony hybridization method for screening in situ of eukaryotic amplified genes

A new method for autoradiographic screening of amplified genes in cellular clones is described. The main feature of the device is to keep viable cells from each clone, which can subsequently be regrown. The availability of this biochemical screening method allows screening for recombinants harboring unselectable markers as well.     

Switzerland The Annual Report for 1987 of the Swiss National Science Foundation

Switzerland The Annual Report for 1987 of the Swiss National Science Foundation     

The ATP synthase (F0−F1) complex in oxidative phosphorylation

The transmembrane electrochemical proton gradient generated by the redox systems of the respiratory chain in mitochondria and aerobic bacteria is utilized by proton translocating ATP synthases to catalyze the synthesis of ATP from ADP and P_i. The bacterial and mitochondrial H⁺-ATP synthases both consist of a membranous sector, F₀, which forms a H⁺-channel, and an extramembranous sector, F₁, which is responsible for catalysis. When detached from the membrane, the purified F₁ sector functions mainly as an ATPase. In chloroplasts, the synthesis of ATP is also driven by a proton motive force, and the enzyme complex responsible for this synthesis is similar to the mitochondrial and bacterial ATP synthases. The synthesis of ATP by H⁺-ATP synthases proceeds without the formation of a phosphorylated enzyme intermediate, and involves co-operative interactions between the catalytic subunits.     

Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA(A) receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.     

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.     

Radiation embryology

Prenatal development, characterized by intensive cell proliferation, cell differentiation and cell migration, shows a high radiosensitivity. Therefore, radiation exposure of embryos and fetuses is of great concern for radiological protection and human health. Irradiation during gestation can cause death, growth disorders, malformations, functional impairment and malignant diseases in childhood. These effects are strongly dependent on the developmental stage at exposure and on the radiation dose. The first trimester of pregnancy is regarded as the period with the highest risk for malformation and cancer induction. The developing nervous system shows a special susceptibility to ionizing radiation over a long period and is therefore of great significance for risk estimation. Knowledge about radiation effects on prenatal development has been derived from animal experimentation and from the exposure of human embryos. There is evidence that doses between 1 and 10 cGy may lead to developmental anomalies and that the radiation response can be modified by additional factors.     

Cyclic nucleotides vs. adenosine analogs as inhibitors of adenylate cyclase activity: Nonidentity of sites of action

Zusammenfassung Substitution einerN ⁶-Aminogruppe eines zyklischen Nukleotids führt zu einer erh?hten Hemmwirkung des Nukleotids gegenüber Adenyl-Cyclase von Meerschweinchenlungen, w?hrend dieN ⁶-Amino-Substition von Adenosin-Analogen eine herabgesetzte Inhibitionswirksamkeit gegenüber demselben Enzym zur Folge hat. Die experimentellen Daten führen zu dem Schluss, dass der Inhibitionsmechanismus gegenüber Cyclase für beide Verbindungstypen verschieden ist.