Inhibiting homologous recombination by targeting RAD51 protein Demeyer, A.; Benhelli-Mokrani, H.; Chénais, B. ...
Biochimica et biophysica acta. Reviews on cancer,
December 2021, 2021-12-00, 20211201, 2021-12, Letnik:
1876, Številka:
2
Journal Article
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Homologous recombination (HR) is involved in repairing DNA double-strand breaks (DSB), the most harmful for the cell. Regulating HR is essential for maintaining genomic stability. In many forms of ...cancer, overactivation of HR increases tumor resistance to DNA-damaging treatments. RAD51, HR's core protein, is very often over-expressed in these cancers and plays a critical role in cancer cell development and survival. Targeting RAD51 directly to reduce its activity and its expression is therefore one strategy to sensitize and overcome resistance cancer cells to existing DNA-damaging therapies which remains the limiting factor for the success of targeted therapy.
This review describes the structure and biological roles of RAD51, summarizes the different targeted sites of RAD51 and its inhibitory compounds discovered and described in the last decade.
Multimodel combination is a pragmatic approach to estimating model uncertainties and to making climate projections more reliable. The simplest way of constructing a multimodel is to give one vote to ...each model ("equal weighting"), while more sophisticated approaches suggest applying model weights according to some measure of performance ("optimum weighting"). In this study, a simple conceptual model of climate change projections is introduced and applied to discuss the effects of model weighting in more generic terms. The results confirm that equally weighted multimodels on average outperform the single models, and that projection errors can in principle be further reduced by optimum weighting. However, this not only requires accurate knowledge of the single model skill, but the relative contributions of the joint model error and unpredictable noise also need to be known to avoid biased weights. If weights are applied that do not appropriately represent the true underlying uncertainties, weighted multimodels perform on average worse than equally weighted ones, which is a scenario that is not unlikely, given that at present there is no consensus on how skill-based weights can be obtained. Particularly when internal variability is large, more information may be lost by inappropriate weighting than could potentially be gained by optimum weighting. These results indicate that for many applications equal weighting may be the safer and more transparent way to combine models. However, also within the presented framework eliminating models from an ensemble can be justified if they are known to lack key mechanisms that are indispensable for meaningful climate projections.
Background
Dysfunctional mitochondria have an influence on inflammation and increased oxidative stress due to an excessive production of reactive oxygen species. The mitochondrial DNA copy number ...(mtDNA‐CN) is a potential biomarker for mitochondrial dysfunction and has been associated with various diseases. However, results were partially contrasting which might have been caused by methodological difficulties to quantify mtDNA‐CN.
Objective
We aimed to investigate whether mtDNA‐CN is associated with peripheral arterial disease (PAD) as well as all‐cause mortality and cardiovascular events during seven years of follow‐up.
Methods
A total of 236 male patients with PAD from the Cardiovascular Disease in Intermittent Claudication (CAVASIC) study were compared with 249 age‐ and diabetes‐matched controls. MtDNA‐CN was measured with a well‐standardized plasmid‐normalized quantitative PCR‐based assay determining the ratio between mtDNA‐CN and nuclear DNA.
Results
Individuals in the lowest quartile of mtDNA‐CN had a twofold increased risk for PAD which, however, was no longer significant after adjusting for leukocytes and platelets. About 67 of the 236 patients had already experienced a cardiovascular event at baseline and those in the lowest mtDNA‐CN quartile had a 2.34‐fold increased risk for these events (95% CI 1.08–5.13). During follow‐up, 37 PAD patients died and 66 patients experienced a cardiovascular event. Patients in the lowest mtDNA‐CN quartile had hazard ratios of 2.66 (95% CI 1.27–5.58) for all‐cause‐mortality and 1.82 (95% CI 1.02–3.27) for cardiovascular events compared with the combined quartile 2–4 (adjusted for age, smoking, CRP, diabetes, prevalent cardiovascular disease, leukocytes and platelets).
Conclusion
This investigation supports the hypothesis of mitochondrial dysfunction in peripheral arterial disease and shows an association of low mtDNA‐CNs with all‐cause‐mortality and prevalent and incident cardiovascular disease in PAD patients with intermittent claudication.
Abstract
The Brier skill score (BSS) and the ranked probability skill score (RPSS) are widely used measures to describe the quality of categorical probabilistic forecasts. They quantify the extent to ...which a forecast strategy improves predictions with respect to a (usually climatological) reference forecast. The BSS can thereby be regarded as the special case of an RPSS with two forecast categories. From the work of Müller et al., it is known that the RPSS is negatively biased for ensemble prediction systems with small ensemble sizes, and that a debiased version, the RPSSD, can be obtained quasi empirically by random resampling from the reference forecast. In this paper, an analytical formula is derived to directly calculate the RPSS bias correction for any ensemble size and combination of probability categories, thus allowing an easy implementation of the RPSSD. The correction term itself is identified as the “intrinsic unreliability” of the ensemble prediction system. The performance of this new formulation of the RPSSD is illustrated in two examples. First, it is applied to a synthetic random white noise climate, and then, using the ECMWF Seasonal Forecast System 2, to seasonal predictions of near-surface temperature in several regions of different predictability. In both examples, the skill score is independent of ensemble size while the associated confidence thresholds decrease as the number of ensemble members and forecast/observation pairs increase.
There are numerous reasons for calculating forecast verification scores, and considerable attention has been given to designing and analyzing the properties of scores that can be used for scientific ...purposes. Much less attention has been given to scores that may be useful for administrative reasons, such as communicating changes in forecast quality to bureaucrats and providing indications of forecast quality to the general public. The two-alternative forced choice (2AFC) test is proposed as a scoring procedure that is sufficiently generic to be usable on forecasts ranging from simple yes-no forecasts of dichotomous outcomes to forecasts of continuous variables, and can be used with deterministic or probabilistic forecasts without seriously reducing the more complex information when available. Although, as with any single verification score, the proposed test has limitations, it does have broad intuitive appeal in that the expected score of an unskilled set of forecasts (random guessing or perpetually identical forecasts) is 50%, and is interpretable as an indication of how often the forecasts are correct, even when the forecasts are expressed probabilistically and/or the observations are not discrete. PUBLICATION ABSTRACT
Rat liver sinusoidal endothelial cells (LECs) express two hyaluronan (HA) receptors, of 175 and 300 kDa, responsible for the endocytic clearance of HA. We have characterized eight monoclonal ...antibodies (mAbs) raised against the 175-kDa HA receptor partially purified from rat LECs. These mAbs also cross-react with the 300-kDa HA receptor. The 175-kDa HA receptor is a single protein, whereas the 300-kDa species contains three subunits, α, β, and γ at 260, 230, and 97 kDa, respectively (Zhou, B., Oka, J. A., and Weigel, P. H. (1999) J. Biol. Chem. 274, 33831–33834). The 97-kDa subunit was not recognized by any of the mAbs in Western blots. Based on their cross-reactivity with these mAbs, the 175-, 230-, and 260-kDa proteins appear to be related. Two of the mAbs inhibit 125I-HA binding and endocytosis by LECs at 37 °C. All of these results confirm that the mAbs recognize thebone fide LEC HA receptor. Indirect immunofluoresence shows high protein expression in liver sinusoids, the venous sinuses of the red pulp in spleen, and the medullary sinuses of lymph nodes. Because the tissue distribution for this endocytic HA receptor is not unique to liver, we propose the name HARE (HAreceptor for endocytosis).
Animal cells internalize specific extracellular macromolecules (ligands) by using specialized cell surface receptors that operate through a complex and highly regulated process known as ...receptor-mediated endocytosis, which involves the binding, internalization, and transfer of ligands through a series of distinct intracellular compartments. For the uptake of a variety of carbohydrate-containing macromolecules, such as glycoproteins, animal cells use specialized membrane-bound lectins as endocytic receptors that recognize different sugar residues or carbohydrate structures present on various ligands. The hepatic asialoglycoprotein receptor, which recognizes glycoconjugates containing terminal galactose or N-acetylgalactosamine residues, was the first membrane lectin discovered and has been a classical system for studying receptor-mediated endocytosis. Studies of how the asialoglycoprotein receptor functions have led to the discovery of two functionally distinct, parallel pathways of clathrin-mediated endocytosis (called the State 1 and State 2 pathways), which may also be utilized by all the other endocytic recycling receptor systems. Another endocytic membrane lectin, the hyaluronan/chondroitin sulfate receptor, which has recently been purified and cloned, is responsible for the turnover in mammals of these glycosaminoglycans, which are important components of extracellular matrices. We discuss the characteristics and physiological importance of these two proteins as examples of how lectins can function as endocytic receptors.
Infection by retroviruses as HIV-1 requires the stable integration of their genome into the host cells. This process needs the formation of integrase (IN)-viral DNA complexes, called intasomes, and ...their interaction with the target DNA wrapped around nucleosomes within cell chromatin. To provide new tools to analyze this association and select drugs, we applied the AlphaLISA technology to the complex formed between the prototype foamy virus (PFV) intasome and nucleosome reconstituted on 601 Widom sequence. This system allowed us to monitor the association between both partners and select small molecules that could modulate the intasome/nucleosome association. Using this approach, drugs acting either on the DNA topology within the nucleosome or on the IN/histone tail interactions have been selected. Within these compounds, doxorubicin and histone binders calixarenes were characterized using biochemical,
molecular simulations and cellular approaches. These drugs were shown to inhibit both PFV and HIV-1 integration
. Treatment of HIV-1-infected PBMCs with the selected molecules induces a decrease in viral infectivity and blocks the integration process. Thus, in addition to providing new information about intasome-nucleosome interaction determinants, our work also paves the way for further unedited antiviral strategies that target the final step of intasome/chromatin anchoring. IMPORTANCE In this work, we report the first monitoring of retroviral intasome/nucleosome interaction by AlphaLISA. This is the first description of the AlphaLISA application for large nucleoprotein complexes (>200 kDa) proving that this technology is suitable for molecular characterization and bimolecular inhibitor screening assays using such large complexes. Using this system, we have identified new drugs disrupting or preventing the intasome/nucleosome complex and inhibiting HIV-1 integration both
and in infected cells. This first monitoring of the retroviral/intasome complex should allow the development of multiple applications including the analyses of the influence of cellular partners, the study of additional retroviral intasomes, and the determination of specific interfaces. Our work also provides the technical bases for the screening of larger libraries of drugs targeting specifically these functional nucleoprotein complexes, or additional nucleosome-partner complexes, as well as for their characterization.
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