HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression.

Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.

HDAC10 blockade upregulates SPARC expression thereby repressing melanoma cell growth and BRAF inhibitor resistance.

Secreted Protein Acidic and Rich in Cysteine (SPARC), a highly conserved secreted glycoprotein, is crucial for various bioprocesses. Here we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression. HDAC10 depletion or inhibition upregulates, while overexpression of HDAC10 downregulates, SPARC expression. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the acetylation state of histone H3 lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth, primarily by induction of autophagy via activation of AMPK signaling. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitivity of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through epigenetic modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC. Highlights: HDAC10 is the primary HDAC member that tightly controls SPARC expression. HDAC10 coordinates with p300 in modulating the H3K27ac state at SPARC regulatory elements and the recruitment of BRD4 to these regions. HDAC10 depletion and resultant SPARC upregulation inhibit melanoma cell growth by inducing autophagy via activation of AMPK signaling.SPARC upregulation as a result of HDAC10 depletion resensitizes resistant cells to BRAF inhibitors.

Past and projected future patterns of fractional vegetation coverage in China.

With the intensifying climate change and the strengthening ecosystem management, quantifying the past and predicting the future influence of these two factors on vegetation change patterns in China need to be analyzed urgently. By constructing a framework model to accurately identify fractional vegetation coverage (FVC) change patterns, we found that FVC in China from 1982 to 2018 mainly showed linear increase (29.5 %) or Gaussian decrease (27.4 %). FVC variation was mainly affected by soil moisture in the Qi-North region and by vapor pressure deficit in other regions. The influence of environmental change on FVC, except for Yang-Qi region in the southwest (-2.0 %), played a positive role, and weakened from the middle (Hu-Yang region: 2.7 %) to the northwest (Qi-North region: 2.4 %) to the east (Hu-East region: 0.8 %). Based on five machine learning algorithms, it was predicted that under four Shared Socioeconomic Pathways (SSPs, including SSP126、SSP245、SSP370、SSP585) from 2019 to 2060, FVC would maintain an upward trend, except for the east, where FVC would rapidly decline after 2039. FVC in the eastern region experienced a transition from past growth to future decline, suggesting that the focus of future ecosystem management should be on this region.

Shift in the migration trajectory of the green biomass loss barycenter in Central Asia.

Revealing the vegetation response law under drought stress has become a hot issue in global climate change research. Against the background of human beings actively responding to climate change, quantitatively revealing the change and migration laws of green biomass loss (GBL) caused by drought in historical and future periods is insufficient. In this regard, we innovatively constructed a joint kNDVI-SPEI (kernel normalized difference vegetation index and standardized precipitation evapotranspiration index) distribution based on copula theory to accurately capture GBL dynamic under various drought scenarios unlike previous studies conducted in a deterministic way. Taking the drought-sensitive and ecologically vulnerable Central Asia (CA) as a typical region, we verified that an average 94.4 % of region showed greater vegetation vulnerability in times of water shortage from May to October, which exhibited the greatest probability of GBL under different drought scenarios, mainly in Kazakhstan and Uzbekistan. Significantly intensified drought due to high emissions will cause an 18.16 percentage-point increase in GBL probability in the far future (FFP, 2061-2100) compared to the near future (NFP, 2019-2060), which is much higher than in the lower-emission (0.38 %) and moderate-emission scenarios (9.82 %). In the NFP, the GBL barycenter will shift from Kazakhstan to Xinjiang, China; in the FFP, it will shift back to Kazakhstan due to the measures taken by the Chinese government to conserve energy and reduce emissions. Results illustrate that against the background of worsening drought, active climate change coping strategies can reverse the migration trajectory of the GBL barycenter caused by drought, which provides a new idea for vegetation protection research in response to global climate change.

A novel multi-model fusion framework diagnoses the complex variation characteristics of ecological indicators and quantitatively reveals their driving mechanism.

Systematic analysis of the change law and driving mechanism of ecological indicators (GPP, ET, WUE), as well as the study of maximum threshold of water resources benefit changing with ecological benefit, are important prerequisites for realizing the scientific allocation and efficient utilization of water resources in desert riparian forests. However, previous studies have defects in the detailed description of the change characteristics of ecological indicators. How to accurately diagnose the characteristics of a site, mutation year, pattern (linear, exponential, logarithmic, etc.), duration of change, future change trends of ecological indicators in a desert riparian environment, as well as quantitatively revealing their driving mechanisms, are major scientific problems that need to be solved urgently. In this regard, an ensemble function coupling a logistic function and an asymmetric Gaussian function was creatively adopted, a novel framework was created to integrate the time-series trajectory fitting method and the sensitivity analysis method, and the arid and ecologically fragile Tarim River Basin was taken as a typical area. The results showed that with enhanced water resource management in the Tarim River Basin, GPP, ET, and WUE all showed patterns of increasing change and could be expected to continue to rise or to remain at a high-level stable state. The longest continuous period of GPP change was 15 years, showing that ecological restoration is a long-term process. The years of GPP mutation were consistent with the implementation periods of major measures in the Tarim River Basin (1990, 2001, and 2011), indicating the reliability of this framework. More importantly, when GPP increased to 216.44 gCm-2, the maximum WUE threshold of 0.93 gCm-2mm-1 occurred. This threshold can be used as a reference criterion for efficient utilization of ecological water in the basin. Among the ecological indicators studied, GPP was the most sensitive to environmental change, but GPP, with 80.60% of pixel area, showed a weak memory effect（α < 0.4). Besides, GPP was the most sensitive to the leaf area index (LAI) and had the strongest correlation with it (p < 0.001). Therefore, LAI can be used as the main control factor for judging plant growth. This research can provide important scientific guidance and reference for the analysis of ecological indicator changes and the sustainable utilization of water resources in arid areas.

Do Extreme Climate Events Cause the Degradation of Malus sieversii Forests in China?

Frequent extreme climate events have attracted considerable attention around the world. Malus sieversii in Xinjiang is the ancestor of cultivated apple, and it is mainly distributed in the Ili river valley at end of the Tianshan Mountains. Wild fruit forests have been degraded, but the cause remains unclear. In order to identify whether extreme climate events caused this degradation reanalysis data and atmospheric circulation indices were used to determine the trends and the reasons for extreme climate changes. Subsequently, we further investigated the effect of extreme climate events on wild fruit forest using characteristics of extreme climate indices and tree-ring chronology. We found increasing trends in both extreme precipitation and warm indices, and decreasing trends in cool indices. Extreme climate events were mainly associated with the Atlantic Multidecadal Oscillation (AMO). Analysis of data of wind and geopotential height field at 500 hPa showed that strengthening wind, increasing geopotential height, cyclone and anti-cyclone circulation drivers contributed to extreme climate events. In the non-degraded region, there were significant positive correlations between tree-ring chronology and both extreme precipitation and extreme warm indices (except for warm spell duration indicator). The other extreme indices (except for heavy rain days) had a large correlation range with tree-rings in a 4-8-year period. These results indicated that extreme precipitation and extreme warm indices intensified M. sieversii growth of the non-degraded region on multi-time scales. In contrast, the degraded region showed insignificant negative relationship between tree-ring chronology and both extreme precipitation and extreme warm indices [except for warm spell duration index (WSDI)], and significant negative correlations in a 4-8-year period were detected between tree-ring chronology and most of the extreme precipitation indices, including heavy rain days, very wet days, cold spell duration indicator, simple precipitation intensity index (SDII), and annual total precipitation. Under the long disturbance of inappropriate anthropic activities, extreme climate has caused the outbreak of pests and diseases resulting in the degeneration of wild fruit forest. Our study provides scientific guidance for the ecosystem conservation in wild fruit forest in China, and also across the region.

EGFR phosphorylates HDAC1 to regulate its expression and anti-apoptotic function.

HDAC1 is the prototypical human histone deacetylase (HDAC) enzyme responsible for catalyzing the removal of acetyl group from lysine residues on many substrate proteins. By deacetylating histones and non-histone proteins, HDAC1 has a profound effect on the regulation of gene transcription and many processes related to cell growth and cell death, including cell cycle progression, DNA repair, and apoptosis. Early studies reveal that, like most eukaryotic proteins, the functions and activities of HDAC1 are regulated by post-translational modifications. For example, serine phosphorylation of HDAC1 by protein kinase CK2 promotes HDAC1 deacetylase enzymatic activity and alters its interactions with proteins in corepressor complexes. Here, we describe an alternative signaling pathway by which HDAC1 activities are regulated. Specifically, we discover that EGFR activity promotes the tyrosine phosphorylation of HDAC1, which is necessary for its protein stability. A key EGFR phosphorylation site on HDAC1, Tyr72, mediates HDAC1's anti-apoptotic function. Given that HDAC1 overexpression and EGFR activity are strongly related with tumor progression and cancer cell survival, HDAC1 tyrosine phosphorylation may present a possible target to manipulate HDAC1 protein levels in future potential cancer treatment strategies.

Variance of vegetation coverage and its sensitivity to climatic factors in the Irtysh River basin.

BACKGROUND: Climate change is an important factor driving vegetation changes in arid areas. Identifying the sensitivity of vegetation to climate variability is crucial for developing sustainable ecosystem management strategies. The Irtysh River is located in the westerly partition of China, and its vegetation cover is more sensitive to climate change. However, previous studies rarely studied the changes in the vegetation coverage of the Irtysh River and its sensitivity to climate factors from a spatiotemporal perspective. METHODS: We adopted a vegetation sensitivity index based on remote sensing datasets of high temporal resolution to study the sensitivity of vegetation to climatic factors in the Irtysh River basin, then reveal the driving mechanism of vegetation cover change. RESULTS: The results show that 88.09% of vegetated pixels show an increasing trend in vegetation coverage, and the sensitivity of vegetation to climate change presents spatial heterogeneity. Sensitivity of vegetation increases with the increase of coverage. Temperate steppe in the northern mountain and herbaceous swamp and broadleaf forest in the river valley, where the normalized difference vegetation index is the highest, show the strongest sensitivity, while the desert steppe in the northern plain, where the NDVI is the lowest, shows the strongest memory effect (or the strongest resilience). Relatively, the northern part of this area is more affected by a combination of precipitation and temperature, while the southern plains dominated by desert steppe are more sensitive to precipitation. The central river valley dominated by herbaceous swamp is more sensitive to temperature-vegetation dryness index. This study underscores that the sensitivity of vegetation cover to climate change is spatially differentiated at the regional scale.

N:P stoichiometric changes via species turnover in arid versus saline desert environments.

Aridity and salinity have a key role in driving physiological and ecological processes in desert ecosystems. However, how community-scale foliar nutrients respond to aridity and salinity, and how these responses might vary with community composition along aridity and salinity gradients is unclear. We hypothesize that the response will be a shift in community stoichiometric values resulting from nutrient variability of shared species and unique species (site-specific species), but little research has addressed the relative contribution of either component.We analyzed the community-scale stoichiometric response of a desert community of perennial plants along an aridity and salinity transect by focusing on foliar nitrogen (N) and phosphorous (P) concentrations and N:P ratios. After evaluating the shared and unique species variability, we determined their relative contribution to the community stoichiometric response to aridity and salinity, reflected by changes in nonweighted and weighted community-average values.Community-scale stoichiometry decreased significantly under aridity and salinity, with significantly consistent changes in nonweighted and weighted community-average stoichiometry for most shared and unique species measurements. The relative contribution of unique species shifts to the changes in community stoichiometry was greater (15%-77%) than the relative contribution of shared species shifts (7%-45%), excluding the change in weighted P concentration under aridity. Thus, the shifts of unique species amplified the community stoichiometric response to environmental changes. Synthesis. These results highlighted the need for a more in-depth consideration of shared and unique species variability to understand and predict the effects of environmental change on the stoichiometry of plant communities. Although variation in community stoichiometry can be expected under extreme aridity and salinity conditions, changes of unique species could be a more important driver of the stoichiometric response of plant communities.

Regulation of poly(a)-specific ribonuclease activity by reversible lysine acetylation.

Poly(A)-specific ribonuclease (PARN) is a 3'-exoribonuclease that plays an important role in regulating the stability and maturation of RNAs. Recently, PARN has been found to regulate the maturation of the human telomerase RNA component (hTR), a noncoding RNA required for telomere elongation. Specifically, PARN cleaves the 3'-end of immature, polyadenylated hTR to form the mature, nonpolyadenylated template. Despite PARN's critical role in mediating telomere maintenance, little is known about how PARN's function is regulated by post-translational modifications. In this study, using shRNA- and CRISPR/Cas9-mediated gene silencing and knockout approaches, along with 3'-exoribonuclease activity assays and additional biochemical methods, we examined whether PARN is post-translationally modified by acetylation and what effect acetylation has on PARN's activity. We found PARN is primarily acetylated by the acetyltransferase p300 at Lys-566 and deacetylated by sirtuin1 (SIRT1). We also revealed how acetylation of PARN can decrease its enzymatic activity both in vitro, using a synthetic RNA probe, and in vivo, by quantifying endogenous levels of adenylated hTR. Furthermore, we also found that SIRT1 can regulate levels of adenylated hTR through PARN. The findings of our study uncover a mechanism by which PARN acetylation and deacetylation regulate its enzymatic activity as well as levels of mature hTR. Thus, PARN's acetylation status may play a role in regulating telomere length.

Estimates of shifts in ecosystem service values due to changes in key factors in the Manas River basin, northwest China.

The ecosystem service value (ESV) can be quantitatively assessed based on changes in ecosystem services. However, few studies have considered two scientific problems: (1) how to quantify the contributions of factors that drive ecosystem services, and (2) how to improve the spatial variability of ESV distributions. In this study, a geographic information system was used to investigate spatial and temporal changes in three factors, i.e., vegetation cover (VC), human disturbance index (HDI), and temperature vegetation drought index (TVDI), and their effects on the ESV in the Manas River basin. We found that high VC areas were expanding and the HDI was significantly enhanced. The contributions of VC, HDI, and TVDI to the total ESV were 38.0%, 31.6%, and 30.4%, respectively, and the total ESV increased by 3.7%. The cold spots were mainly distributed in the desert area, mountains, and the southern parts of the oasis area, whereas the hot spots occurred mainly to the north of the oasis area and southwest of the desert. VC, HDI, and TVDI reflected the spatial and temporal differences in the ESV determined in this river basin ecosystem. Furtherly, it may be possible to formulate appropriate ecological compensations by analyzing the changes in ESV cold/hot spots. The results of this study provide a scientific basis to facilitate the selection of the key factors that drive changes in the ESV in arid land areas, as well as for achieving a sustainable basin management in similar regions around the world.

Evaluation of the ecological protective effect of the "large basin" comprehensive management system in the Tarim River basin, China.

It is very important to construct a reasonable and efficient basin management system to meet the ecological water demand in arid areas with natural vegetation, and to maintain the integrity and stability of fragile ecosystems. However, how to assess the effect of basin management on ecological protection in arid areas as well as how to achieve the optimal control and efficient use of ecological water are major issues for many researchers and river basin managers. To address these two questions, we investigated the comprehensive management system for the Tarim River basin in China as a typical case study. The results showed that the natural vegetation coverage degree, the ecological water supply, temperature vegetation dryness index (TVDI), and the tree-ring chronology of Populus euphratica increased, whereas the disturbance of water resources by human activities decreased. Therefore, the effects of ecological protection were obvious after comprehensive "large basin" management. Based on an innovative application of tree-ring chronology to estimate the water leakage from the river, we determined the minimum runoff level (43.1 × 108 m3) when the natural vegetation needs to overflow. To further improve the effect of comprehensive management, the optimal regulation mode (i.e. maintaining the groundwater depth at 2-6 m, and the frequency and duration of overflowing at 2-3 times per year for a duration of 15-20 days during July to September) for the ecological sluices was formulated from the perspective of the efficient utilization of ecological water. These results provide a scientific reference for constructing reasonable management systems for similar river basins in arid areas.

Disentangling the influence of aridity and salinity on community functional and phylogenetic diversity in local dryland vegetation.

One of the key hypothesized drivers of community assembly and dynamics is environmental filtering, where environmental stress limits species migration and survival as a result of functional trait convergence. Whereas most such studies focus on large-scale variation in functional traits along a single-factor environmental gradient, the mutual effects of small-scale multiple environmental filtering remain unclear. Furthermore, it has rarely been tested whether the combined effect of aridity and salinity on local dryland vegetation constrains the patterns of functional traits and phylogenetic structures. Across an 8-km long transect in the arid northwest of China, we assessed the role of environmental filtering in shaping community assemblages by testing the hypotheses that aridity and salinity stresses, interspecific competition and phylogenetic structures constrained functional diversity in the local dryland vegetation. Our results showed that aridity significantly increased convergence of the maximum plant height, specific leaf area, leaf area and leaf nitrogen concentration. However, salinity significantly promoted the convergence of only leaf area and leaf nitrogen concentration. In addition, interspecific competition increased the convergence of the maximum plant height and leaf area. Leaf area converged significantly due to phylogenetic history. Aridity filtering, but not salinity filtering, obviously increased the clustering of phylogenetic structure. Interspecific competition and phylogenetic structure had weak effects on functional diversity in local dryland vegetation. In conclusion, compared with salinity filtering, aridity filtering was more important in reducing phylogenetic diversity in dryland vegetation.

Histone Deacetylase SIRT1 Targets Plk2 to Regulate Centriole Duplication.

The protein deacetylase SIRT1 (Sirtuin 1) regulates many cellular processes, including cell-cycle progression, DNA damage response, and metabolism. Although the centrosome is a key regulator of cell-cycle progression and genome stability, little is known concerning SIRT1 controlled centrosome-associated events. Here we report that the centrosome protein Plk2 is acetylated and undergoes deacetylation by SIRT1. Acetylation protects Plk2 from ubiquitination, and SIRT1-mediated deacetylation promotes ubiquitin-dependent degradation of Plk2. SIRT1 controls centriole duplication by temporally modulating centrosomal Plk2 levels. AURKA phosphorylates SIRT1 and promotes the SIRT1-Plk2 interaction in mitosis. In early-mid G1, phosphorylated SIRT1 deacetylates and promotes Plk2 degradation. In late G1, SIRT1 is hypophosphorylated and its affinity to Plk2 is decreased, resulting in a rapid accumulation of centrosomal Plk2, which contributes to the timely initiation of centriole duplication. Collectively, our findings uncover a critical role of SIRT1 in centriole duplication and provide a mechanistic insight into SIRT1-mediated centrosome-associated functions.

Negative feedback adjustment challenges reconstruction study from tree rings: A study case of response of Populus euphratica to river discontinuous flow and ecological water conveyance.

Drought stress changes the relationship between the growth of tree rings and variations in ambient temperature. However, it is not clear how the growth of trees changes in response to drought of varying intensities, especially in arid areas. Therefore, Tree rings were studied for 6years in Populus euphratica to assess the impacts of abrupt changes in environment on tree rings using the theories and methods in dendrohydrology, ecology and phytophysiology. The width of tree rings increased by 8.7% after ecological water conveyance downstream of Tarim River compared to that when the river water had been cut off. However, during intermediate drought, as the depth of the groundwater increases, the downward trend in the tree rings was reversed because of changes in the physiology of the tree. Therefore, the growth of tree rings shows a negative feedback to intermediate drought stress, an observation that challenges the homogenization theory of tree ring reconstruction based on the traditional methods. Owing to the time lag, the cumulative effect and the negative feedback between the growth of tree rings and drought stress, the reconstruction of past environment by studying the patterns of tree rings is often inaccurate. Our research sets out to verify the hypothesis that intermediate drought stress results in a negative feedback adjustment and thus to answers two scientific questions: (1) How does the negative feedback adjustment promote the growth of tree rings as a result of intermediate drought stress? (2) How does the negative feedback adjustment lower the accuracy with which the past is reconstructed based on tree rings? This research not only enriches the connotations of intermediate disturbance hypothesis and reconstruction theory of tree rings, but also provides a scientific basis for the conservation of desert riparian forests worldwide.

Crosstalk between transforming growth factor-ß signaling pathway and long non-coding RNAs in cancer.

The transforming growth factor-ß (TGF-ß) signaling pathway plays an important role in tumorigenesis by exerting either a tumor-suppressing or tumor-promoting effect. Long non-coding RNAs (lncRNAs), a newly discovered class of non-coding RNAs, have been widely studied in recent years and identified as crucial regulators of various biological processes, including cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Recent evidence, addressing the crosstalk between the TGF-ß signaling pathway and lncRNAs in cancer, found that several members of the TGF-ß pathway are targeted by lncRNAs, and the production of hundreds of lncRNAs is induced by TGF-ß treatment. This review will summarize the latest progress on the investigation of TGF-ß pathway and lncRNA network in regulating cancer development. Further study on the network would provide a better understanding of carcinogenesis and have potentials for the prevention and treatment of malignant diseases.

How to Regenerate and Protect Desert Riparian Populus euphratica Forest in Arid Areas.

We found that the most suitable flooding disturbance model for regenerating Populus euphratica forest was two to three times per year with a duration of 15-20 days and an intensity of 25-30 m(3)/s. The flooding should take place during the seed emergence to young tree growth stages, and should be based on flooding experiments and data from vegetation quadrats and ecological water conveyance. Furthermore, we found that tree-ring width index for P. euphratica declined as the groundwater depth increased, and ascertained that the minimum groundwater depths for young trees, near-mature trees, mature trees and over-mature trees were 4.0 m, 5.0-5.4 m, 6.9 m and 7.8 m, respectively. These were derived from a quantitative relationship model between groundwater depth and tree-ring width index. The range for ecological water conveyance volume was 311-320 million m(3) in the lower reaches of the Tarim River. This study not only provides a technical basis for sustainable ecological water conveyance in the Tarim River Basin, but also offers a theoretical guide and scientific information that could be used in similar areas to regenerate and protect Populus euphratica around the world.

Ubiquitinated sirtuin 1 (SIRT1) function is modulated during DNA damage-induced cell death and survival.

Downstream signaling of physiological and pathological cell responses depends on post-translational modification such as ubiquitination. The mechanisms regulating downstream DNA damage response (DDR) signaling are not completely elucidated. Sirtuin 1 (SIRT1), the founding member of Class III histone deacetylases, regulates multiple steps in DDR and is closely associated with many physiological and pathological processes. However, the role of post-translational modification or ubiquitination of SIRT1 during DDR is unclear. We show that SIRT1 is dynamically and distinctly ubiquitinated in response to DNA damage. SIRT1 was ubiquitinated by the MDM2 E3 ligase in vitro and in vivo. SIRT1 ubiquitination under normal conditions had no effect on its enzymatic activity or rate of degradation; hypo-ubiquitination, however, reduced SIRT1 nuclear localization. Ubiquitination of SIRT1 affected its function in cell death and survival in response to DNA damage. Our results suggest that ubiquitination is required for SIRT1 function during DDR.

Functional relationship among PLK2, PLK4 and ROCK2 to induce centrosome amplification.

The presence of more than 2 centrosomes (centrosome amplification) leads to defective mitosis and chromosome segregation errors, is frequently found in a variety of cancer types, and believed to be the major cause of chromosome instability. One mechanism for generation of amplified centrosomes is over-duplication of centrosomes in a single cell cycle, which is expected to occur when cells are temporarily arrested. There are a growing number of kinases that are critical for induction and promotion of centrosome amplification in the cell cycle-arrested cells, including Rho-associated kinase (ROCK2), Polo-like kinase 2 (PLK2) and PLK4. Here, we tested whether these kinases induce centrosome amplification in a linear pathway or parallel pathways. We first confirmed that ROCK2, PLK2 and PLK4 are all essential for centrosomes to re-duplicate in the cells arrested by exposure to DNA synthesis inhibitor. Using the centrosome amplification rescue assay, we found that PLK2 indirectly activates ROCK2 via phosphorylating nucleophosmin (NPM), and PLK4 functions downstream of ROCK2 to drive centrosome amplification in the arrested cells.

Novel nikkomycin analogues generated by mutasynthesis in Streptomyces ansochromogenes.

BACKGROUND: Nikkomycins are competitive inhibitors of chitin synthase and inhibit the growth of filamentous fungi, insects, acarids and yeasts. The gene cluster responsible for biosynthesis of nikkomycins has been cloned and the biosynthetic pathway was elucidated at the genetic, enzymatic and regulatory levels. RESULTS: Streptomyces ansochromogenes ΔsanL was constructed by homologous recombination and the mutant strain was fed with benzoic acid, 4-hydroxybenzoic acid, nicotinic acid and isonicotinic acid. Two novel nikkomycin analogues were produced when cultures were supplemented with nicotinic acid. These two compounds were identified as nikkomycin Px and Pz by electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR). Bioassays against Candida albicans and Alternaria longipes showed that nikkomycin Px and Pz exhibited comparatively strong inhibitory activity as nikkomycin X and Z produced by Streptomyces ansochromogenes 7100 (wild-type strain). Moreover, nikkomycin Px and Pz were found to be more stable than nikkomycin X and Z at different pH and temperature conditions. CONCLUSIONS: Two novel nikkomycin analogues (nikkomycin Px and Pz) were generated by mutasynthesis with the sanL inactivated mutant of Streptomyces ansochromogenes 7100. Although antifungal activities of these two compounds are similar to those of nikkomycin X and Z, their stabilities are much better than nikkomycin X and Z under different pHs and temperatures.