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1.
The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection—the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability.  相似文献   
2.
Based on a non-equilibrium mechanism for spatial pattern formation we study how position information can be controlled by locally coupled discrete dynamical networks, similar to gene regulation networks of cells in a developing multicellular organism. As an example we study the developmental problems of domain formation and proportion regulation in the presence of noise, as well as in the presence of cell flow. We find that networks that solve this task exhibit a hierarchical structure of information processing and are of similar complexity as developmental circuits of living cells. Proportion regulation is scalable with system size and leads to sharp, precisely localized boundaries of gene expression domains, even for large numbers of cells. A detailed analysis of noise-induced dynamics, using a mean-field approximation, shows that noise in gene expression states stabilizes (rather than disrupts) the spatial pattern in the presence of cell movements, both for stationary as well as growing systems. Finally, we discuss how this mechanism could be realized in the highly dynamic environment of growing tissues in multicellular organisms.  相似文献   
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4.
Ubiquitin and UBL (ubiquitin-like) modifiers are small proteins that covalently modify other proteins to alter their properties or behaviours. Ubiquitin modification (ubiquitylation) targets many substrates, often leading to their proteasomal degradation. NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is the UBL most closely related to ubiquitin, and its best-studied role is the activation of CRLs (cullin-RING ubiquitin ligases) by its conjugation to a conserved C-terminal lysine residue on cullin proteins. The attachment of UBLs requires three UBL-specific enzymes, termed E1, E2 and E3, which are usually well insulated from parallel UBL pathways. In the present study, we report a new mode of NEDD8 conjugation (NEDDylation) whereby the UBL NEDD8 is linked to proteins by ubiquitin enzymes in vivo. We found that this atypical NEDDylation is independent of classical NEDD8 enzymes, conserved from yeast to mammals, and triggered by an increase in the NEDD8 to ubiquitin ratio. In cells, NEDD8 overexpression leads to this type of NEDDylation by increasing the concentration of NEDD8, whereas proteasome inhibition has the same effect by depleting free ubiquitin. We show that bortezomib, a proteasome inhibitor used in cancer therapy, triggers atypical NEDDylation in tissue culture, which suggests that a similar process may occur in patients receiving this treatment.  相似文献   
5.
Cullin‐based E3 ubiquitin ligases are activated through covalent modification of the cullin subunit by the ubiquitin‐like protein Nedd8. Cullin neddylation dissociates the ligase assembly inhibitor Cand1, and promotes E2 recruitment and ubiquitin transfer by inducing a conformational change. Here, we have identified and characterized Lag2 as a likely Saccharomyces cerevisiae orthologue of mammalian Cand1. Similar to Cand1, Lag2 directly interacts with non‐neddylated yeast cullin Cdc53 and prevents its neddylation in vivo and in vitro. Binding occurs through a conserved C‐terminal β‐hairpin structure that inserts into the Skp1‐binding pocket on the cullin, and an N‐terminal motif that covers the neddylation lysine. Interestingly, Lag2 is itself neddylated in vivo on a lysine adjacent to this N‐terminal‐binding site. Overexpression of Lag2 inhibits Cdc53 activity in strains defective for Skp1 or neddylation functions, implying that these activities are important to counteract Lag2 in vivo. Our results favour a model in which binding of substrate‐specific adaptors triggers release of Cand1/Lag2, whereas subsequent neddylation of the cullin facilitates the removal and prevents re‐association of Lag2/Cand1.  相似文献   
6.
BACKGROUND: SCF (Skp1-Cullin-F-box) complexes are a major class of E3 ligases that are required to selectively target substrates for ubiquitin-dependent degradation by the 26S proteasome. Conjugation of the ubiquitin-like protein Nedd8 to the cullin subunit (neddylation) positively regulates activity of SCF complexes, most likely by increasing their affinity for the E2 conjugated to ubiquitin. The Nedd8 conjugation pathway is required in C. elegans embryos for the ubiquitin-mediated degradation of the microtubule-severing protein MEI-1/Katanin at the meiosis-to-mitosis transition. Genetic experiments suggest that this pathway controls the activity of a CUL-3-based E3 ligase. Counteracting the Nedd8 pathway, the COP9/signalosome has been shown to promote deneddylation of the cullin subunit. However, little is known about the role of neddylation and deneddylation for E3 ligase activity in vivo. RESULTS: Here, we identified and characterized the COP9/signalosome in C. elegans and showed that it promotes deneddylation of CUL-3, a critical target of the Nedd8 conjugation pathway. As in other species, the C. elegans signalosome is a macromolecular complex containing at least six subunits that localizes in the nucleus and the cytoplasm. Reducing COP9/signalosome function by RNAi results in a failure to degrade MEI-1, leading to severe defects in microtubule-dependent processes during the first mitotic division. Intriguingly, reducing COP9/signalosome function suppresses a partial defect in the neddylation pathway; this suppression suggests that deneddylation and neddylation antagonize each other. CONCLUSIONS: We conclude that both neddylation and deneddylation of CUL-3 is required for MEI-1 degradation and propose that cycles of CUL-3 neddylation and deneddylation are necessary for its ligase activity in vivo.  相似文献   
7.
The ubiquitin protein conjugation system tags proteins with the small polypeptide ubiquitin. Most poly-ubiquitinated proteins are recognized and degraded by the proteasome, a large multi-subunit protease. Ubiquitin-dependent protein degradation is used as a regulatory tool for many essential processes, the best studied of which is eukaryotic cell cycle progression. More recently, genetic studies in C. elegans have identified multiple roles for the ubiquitin system in early development, where ubiquitin-dependent protein degradation governs such diverse events as passage through meiosis, cytoskeletal regulation and cell fate determination.  相似文献   
8.

Background and aims

We studied the response of lignin oxidation in soils of a beech/oak forest to changes in litter fall. Additionally we considered possible factors in lignin oxidation, including altered (i) input of fresh organic matter and (ii) fungi-to-bacteria ratios.

Methods

The field-based experiment included (i) doubling and (ii) exclusion of litter fall and (iii) controls with ambient litter fall. Soil (0–20 cm depth) was sampled after 8 years. We analyzed (i) lignin using the CuO oxidation method, (ii) stocks of free and mineral-bound organic carbon (OC), (iii) the response of soil organic matter (SOM) decomposition to addition of labile organic compounds in laboratory incubations, and (iv) ratios of fungal- vs. bacterial-derived amino sugars (F/B ratios).

Results

Litter exclusion increased stocks of free-light fraction OC, F/B ratios, the ability of the microbial community to use labile compounds for SOM decomposition, as well as acid-to-aldehyde ratios of vanillyl-type lignin phenols in A horizons. Litter addition had no such effects. We assume that litter exclusion caused enhanced transport of organic debris from lower forest floor horizons with rainwater into the A horizon. Enhanced input of organic debris might have increased (i) the availability of labile compounds and (ii) F/B ratios. Consequently, lignin oxidation increased.

Conclusions

Enhanced input of organic debris from forest floors can increase lignin oxidation in mineral topsoils of the studied forest. The expected gradual changes in litter fall due to climate change likely will cause no such effects.  相似文献   
9.
The aim of this study was to compare the effects of high-intensity interval training (HIIT) and repeated-sprint training (RST) on aerobic fitness, tennis-specific endurance, linear and repeated-sprint ability (RSA), and jumping ability. Thirty-one competitive male tennis players took part in a training intervention of 6 weeks. The players were matched into 3 groups, HIIT (n = 11), RST (n = 12), or control group (CON, n = 9). The results showed significant time × intervention interactions for VO(2)peak, with a significant increase in the VO(2)peak level of 6.0% in HIIT (p = 0.008) and 4.9% in RST (p = 0.010), whereas no changes occurred in CON. However, the following differences were found between the intervention groups: The HIIT-induced greater improvements in tennis-specific endurance (HIIT 28.9% vs. RST 14.5%; p < 0.05) and RST led to a significant improvement in RSA (i.e., reduction in the mean sprint time of 3.8%; p < 0.05). Neither training strategy induced any effects on jumping and sprinting abilities. Both training interventions showed similar improvements in general aerobic fitness. Also, the present results suggest that RST represents a time-efficient stimulus for a simultaneous improvement of general and tennis-specific aerobic fitness as well for RSA.  相似文献   
10.
Current genome-wide ChIP-seq experiments on different epigenetic marks aim at unraveling the interplay between their regulation mechanisms. Published evaluation tools, however, allow testing for predefined hypotheses only. Here, we present a novel method for annotation-independent exploration of epigenetic data and their inter-correlation with other genome-wide features. Our method is based on a combinatorial genome segmentation solely using information on combinations of epigenetic marks. It does not require prior knowledge about the data (e.g. gene positions), but allows integrating the data in a straightforward manner. Thereby, it combines compression, clustering and visualization of the data in a single tool. Our method provides intuitive maps of epigenetic patterns across multiple levels of organization, e.g. of the co-occurrence of different epigenetic marks in different cell types. Thus, it facilitates the formulation of new hypotheses on the principles of epigenetic regulation. We apply our method to histone modification data on trimethylation of histone H3 at lysine 4, 9 and 27 in multi-potent and lineage-primed mouse cells, analyzing their combinatorial modification pattern as well as differentiation-related changes of single modifications. We demonstrate that our method is capable of reproducing recent findings of gene centered approaches, e.g. correlations between CpG-density and the analyzed histone modifications. Moreover, combining the clustered epigenetic data with information on the expression status of associated genes we classify differences in epigenetic status of e.g. house-keeping genes versus differentiation-related genes. Visualizing the distribution of modification states on the chromosomes, we discover strong patterns for chromosome X. For example, exclusively H3K9me3 marked segments are enriched, while poised and active states are rare. Hence, our method also provides new insights into chromosome-specific epigenetic patterns, opening up new questions how “epigenetic computation” is distributed over the genome in space and time.  相似文献   
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