14-3-3 Proteins, FHA Domains and BRCT Domains in the DNA Damage Response

The DNA damage response depends on the concerted activity of protein serine/threonine kinases and modular phosphoserine/threonine-binding domains to relay the damage signal and recruit repair proteins. The PIKK family of protein kinases, which includes ATM/ATR/DNA-PK, preferentially phosphorylate Ser-Gln sites, while their basophilic downstream effecter kinases, Chk1/Chk2/MK2 preferentially phosphorylate hydrophobic-X-Arg-X-X-Ser/Thr-hydrophobic sites. A subset of tandem BRCT domains act as phosphopeptide binding modules that bind to ATM/ATR/DNA-PK substrates after DNA damage. Conversely, 14-3-3 proteins interact with substrates of Chk1/Chk2/MK2. FHA domains have been shown to interact with substrates of ATM/ATR/DNA-PK and CK2. In this review we consider how substrate phsophorylation together with BRCT domains, FHA domains and 14-3-3 proteins function to regulate ionizing radiation-induced nuclear foci and help to establish the G2/M checkpoint. We discuss the role of MDC1 a molecular scaffold that recruits early proteins to foci, such as NBS1 and RNF8, through distinct phosphodependent interactions. In addition, we consider the role of 14-3-3 proteins and the Chk2 FHA domain in initiating and maintaining cell cycle arrest

Genetic modifiers of cognitive maintenance among older adults.

ObjectiveIdentify genetic factors associated with cognitive maintenance in late life and assess their association with gray matter (GM) volume in brain networks affected in aging.MethodsWe conducted a genome-wide association study of ∼2.4 M markers to identify modifiers of cognitive trajectories in Caucasian participants (N = 7,328) from two population-based cohorts of non-demented elderly. Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among participants and mixed model regression was used to determine subject-specific cognitive slopes. "Cognitive maintenance" was defined as a change in slope of ≥ 0 and was compared with all cognitive decliners (slope < 0). In an independent cohort of cognitively normal older Caucasians adults (N = 122), top association findings were then used to create genetic scores to assess whether carrying more cognitive maintenance alleles was associated with greater GM volume in specific brain networks using voxel-based morphometry.ResultsThe most significant association was on chromosome 11 (rs7109806, P = 7.8 × 10(-8)) near RIC3. RIC3 modulates activity of α7 nicotinic acetylcholine receptors, which have been implicated in synaptic plasticity and beta-amyloid binding. In the neuroimaging cohort, carrying more cognitive maintenance alleles was associated with greater volume in the right executive control network (RECN; PFWE  = 0.01).ConclusionsThese findings suggest that there may be genetic loci that promote healthy cognitive aging and that they may do so by conferring robustness to GM in the RECN. Future work is required to validate top candidate genes such as RIC3 for involvement in cognitive maintenance

Cytokine-Induced Signaling Networks Prioritize Dynamic Range over Signal Strength

SummarySignaling networks respond to diverse stimuli, but how the state of the signaling network is relayed to downstream cellular responses is unclear. We modeled how incremental activation of signaling molecules is transmitted to control apoptosis as a function of signal strength and dynamic range. A linear relationship between signal input and response output, with the dynamic range of signaling molecules uniformly distributed across activation states, most accurately predicted cellular responses. When nonlinearized signals with compressed dynamic range relay network activation to apoptosis, we observe catastrophic, stimulus-specific prediction failures. We develop a general computational technique, “model-breakpoint analysis,” to analyze the mechanism of these failures, identifying new time- and stimulus-specific roles for Akt, ERK, and MK2 kinase activity in apoptosis, which were experimentally verified. Dynamic range is rarely measured in signal-transduction studies, but our experiments using model-breakpoint analysis suggest it may be a greater determinant of cell fate than measured signal strength

Exploiting synthetic lethal interactions for targeted cancer therapy

March 15, 2011Emerging data suggests that synthetic lethal interactions between mutated oncogenes/tumor suppressor genes and molecules involved in DNA damage signaling and repair can be therapeutically exploited to preferentially kill tumor cells. In this review, we discuss the concept of synthetic lethality, and describe several recent examples in which this concept was successfully implemented to target tumor cells in culture, in mouse models, and in human cancer patients.National Institutes of Health (U.S.) (Grant GM68762)National Institutes of Health (U.S.) (Grant CA112967)National Institutes of Health (U.S.) (Grant ES015339)National Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant U54-CA112967-03)German Research Foundation (RE2246/1-1)David H. Koch Cancer Research FundGerman Kidney Foundatio

Percolation and Critical Behaviour in SU(2) Gauge Theory

The paramagnetic-ferromagnetic transition in the Ising model can be described as percolation of suitably defined clusters. We have tried to extend such picture to the confinement-deconfinement transition of SU(2) pure gauge theory, which is in the same universality class of the Ising model. The cluster definition is derived by approximating SU(2) by means of Ising-like effective theories. The geometrical transition of such clusters turns out to describe successfully the thermal counterpart for two different lattice regularizations of (3+1)-d SU(2).Comment: Lattice 2000 (Finite Temperature), 4 pages, 4 figures, 2 table

Effective lattice theories for Polyakov loops

We derive effective actions for SU(2) Polyakov loops using inverse Monte Carlo techniques. In a first approach, we determine the effective couplings by requiring that the effective ensemble reproduces the single-site distribution of the Polyakov loops. The latter is flat below the critical temperature implying that the (untraced) Polyakov loop is distributed uniformly over its target space, the SU(2) group manifold. This allows for an analytic determination of the Binder cumulant and the distribution of the mean-field, which turns out to be approximately Gaussian. In a second approach, we employ novel lattice Schwinger-Dyson equations which reflect the SU(2) x SU(2) invariance of the functional Haar measure. Expanding the effective action in terms of SU(2) group characters makes the numerics sufficiently stable so that we are able to extract a total number of 14 couplings. The resulting action is short-ranged and reproduces the Yang-Mills correlators very well.Comment: 27 pages, 8 figures, v2: method refined, chapter and references adde

Wigner--Dyson statistics for a class of integrable models

We construct an ensemble of second--quantized Hamiltonians with two bosonic degrees of freedom, whose members display with probability one GOE or GUE statistics. Nevertheless, these Hamiltonians have a second integral of motion, namely the boson number, and thus are integrable. To construct this ensemble we use some ``reverse engineering'' starting from the fact that $n$--bosons in a two--level system with random interactions have an integrable classical limit by the old Heisenberg association of boson operators to actions and angles. By choosing an $n$--body random interaction and degenerate levels we end up with GOE or GUE Hamiltonians. Ergodicity of these ensembles completes the example.Comment: 3 pages, 1 figur

Fermion Production in the Background of Minkowski Space Classical Solutions in Spontaneously Broken Gauge Theory

We investigate fermion production in the background of Minkowski space solutions to the equations of motion of $SU(2)$ gauge theory spontaneously broken via the Higgs mechanism. First, we attempt to evaluate the topological charge $Q$ of the solutions. We find that for solutions $Q$ is not well-defined as an integral over all space-time. Solutions can profitably be characterized by the (integer-valued) change in Higgs winding number $\Delta N_H$. We show that solutions which dissipate at early and late times and which have nonzero $\Delta N_H$ must have at least the sphaleron energy. We show that if we couple a quantized massive chiral fermion to a classical background given by a solution, the number of fermions produced is $\Delta N_H$, and is not related to $Q$.Comment: Version to be published. Argument showing that the topological charge of solutions is undefined has been strengthened and clarified. Conclusions unchange