scholarly journals The deacetylation-phosphorylation regulation of SIRT2-SMC1A axis as a mechanism of antimitotic catastrophe in early tumorigenesis

2021 ◽  
Vol 7 (9) ◽  
pp. eabe5518
Author(s):  
Fei Yi ◽  
Ying Zhang ◽  
Zhijun Wang ◽  
Zhuo Wang ◽  
Ziwei Li ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Early Stage ◽  
Chemotherapeutic Agents ◽  
Mass Spectrometry Analysis ◽  
Mitotic Catastrophe ◽  
Precursor Lesions ◽  
Spectrometry Analysis ◽  
Higher Eukaryotes ◽  
Structural Maintenance Of Chromosomes ◽  
Oncogenic Stress

Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.

scholarly journals Diagnosis of Parkinson’s Disease by A Metabolomics-Based Laboratory-Developed Test (LDT)

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 332 ◽  
Author(s):  
Petr G. Lokhov ◽  
Oxana P. Trifonova ◽  
Dmitry L. Maslov ◽  
Steven Lichtenberg ◽  
Elena E. Balashova
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Stage ◽  
Mass Spectrometry Analysis ◽  
Great Effort ◽  
Spectrometry Analysis ◽  
Yahr Scale ◽  
In Vitro Diagnostic ◽  
Stage 1

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is designed, manufactured and used in the same laboratory (i.e., an in-house test). In this study, a metabolomics-based LDT was developed. This test involves a blood plasma preparation, direct-infusion mass spectrometry analysis with a high-resolution mass spectrometer, alignment and normalization of mass peaks using original algorithms, metabolite annotation by a biochemical context-driven algorithm, detection of overrepresented metabolic pathways and results in a visualization in the form of a pathway names cloud. The LDT was applied to detect early stage Parkinson’s disease (PD)—the diagnosis of which currently requires great effort due to the lack of available laboratory tests. In a case–control study (n = 56), the LDT revealed a statistically sound pattern in the PD-relevant pathways. Usage of the LDT for individuals confirmed its ability to reveal this pattern and thus diagnose PD at the early-stage (1–2.5 stages, according to Hoehn and Yahr scale). The detection of this pattern by LDT could diagnose PD with a specificity of 64%, sensitivity of 86% and an accuracy of 75%. Thus, this LDT can be used for further widespread testing.

scholarly journals Phospho-regulation of the Shugoshin - Condensin interaction at the centromere in budding yeast

2019 ◽  
Author(s):  
Galal Yahya Metwaly ◽  
Yehui Wu ◽  
Karolina Peplowska ◽  
Jennifer Röhrl ◽  
Young-Min Soh ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Budding Yeast ◽  
Spindle Assembly ◽  
Mass Spectrometry Analysis ◽  
Spectrometry Analysis ◽  
Spindle Poles ◽  
Condensin Complex ◽  
Centromeric Protein

AbstractCorrect bioriented attachment of sister chromatids to mitotic spindle is essential for chromosome segregation. The conserved protein shugoshin (Sgo1) contributes in budding yeast to biorientation by recruiting the protein phosphatase PP2A-Rts1 and the condensin complex to centromeres. Using peptide prints, we identified a Serine-Rich Motif (SRM) of Sgo1 that mediates the interaction with condensin and is essential for centromeric condensin recruitment and the establishment of biorientation. We show that the interaction is regulated via phosphorylation within the SRM and we determined the phospho-sites using mass spectrometry. Analysis of the phosphomimicking and phosphoresistant mutants revealed that SRM phosphorylation disrupts the shugoshin – condensin interaction. We present an evidence that Mps1, a central kinase in the spindle assembly checkpoint, directly phosphorylates Sgo1 within the SRM to regulate the interaction with condensin and thereby condensin localization to centromeres. Our findings identify novel mechanisms that control shugoshin activity at the centromere in budding yeast.Author summaryProper chromosome segregation in eukaryotes is ensured through correct attachment of the spindle microtubules to the centromeric chromosomal regions. The attachment is mediated via the multimolecular proteinaceous complex called kinetochore and precisely regulated. This enables the establishment of so called bioirentation, when each sister chromatid is attached to microtubules emanating from opposite spindle poles. Shugoshin (Sgo1) is a conserved centromeric protein that facilitates biorientation through its interactions with the protein phosphatase PP2A/Rts1, chromosome passanger complex and centromeric condensin. Here, we identified a serin-rich motif that is required for the interaction of shugoshin with the condensin complex. We show that loss of this region impairs condensin enrichment at the centromere, chromosome biorientation, segregation as well as the function of the chromosome passanger complex in the error correction. Moreover, the interaction is phosphoregulated, as phosphorylation of the serin-rich motif on Sgo1 disrupts its interaction with condensin. Finally, we show that the conserved spindle assembly checkpoint kinase Mps1 is responsible for this phosphorylation. Our findings uncover novel regulatory mechanisms that facilitate proper chromosome segregation.

scholarly journals Cell cycle–dependent association of polo kinase Cdc5 with CENP-A contributes to faithful chromosome segregation in budding yeast

2019 ◽  
Vol 30 (8) ◽  
pp. 1020-1036 ◽  
Author(s):  
Prashant K. Mishra ◽  
Gudjon Olafsson ◽  
Lars Boeckmann ◽  
Timothy J. Westlake ◽  
Ziad M. Jowhar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Mass Spectrometry Analysis ◽  
Spectrometry Analysis ◽  
Growth Defects ◽  
Evolutionarily Conserved ◽  
Histone H3 Variant ◽  
Cycle Dependent

Evolutionarily conserved polo-like kinase, Cdc5 (Plk1 in humans), associates with kinetochores during mitosis; however, the role of cell cycle–dependent centromeric ( CEN) association of Cdc5 and its substrates that exclusively localize to the kinetochore have not been characterized. Here we report that evolutionarily conserved CEN histone H3 variant, Cse4 (CENP-A in humans), is a substrate of Cdc5, and that the cell cycle–regulated association of Cse4 with Cdc5 is required for cell growth. Cdc5 contributes to Cse4 phosphorylation in vivo and interacts with Cse4 in mitotic cells. Mass spectrometry analysis of in vitro kinase assays showed that Cdc5 phosphorylates nine serine residues clustered within the N-terminus of Cse4. Strains with cse4-9SA exhibit increased errors in chromosome segregation, reduced levels of CEN-associated Mif2 and Mcd1/Scc1 when combined with a deletion of MCM21. Moreover, the loss of Cdc5 from the CEN chromatin contributes to defects in kinetochore integrity and reduction in CEN-associated Cse4. The cell cycle–regulated association of Cdc5 with Cse4 is essential for cell viability as constitutive association of Cdc5 with Cse4 at the kinetochore leads to growth defects. In summary, our results have defined a role for Cdc5-mediated Cse4 phosphorylation in faithful chromosome segregation.

scholarly journals SMOKING-RELATED DNA ADDUCTS AS POTENTIAL DIAGNOSTIC MARKERS OF LUNG CANCER: NEW PERSPECTIVES

2015 ◽  
Vol 37 (1) ◽  
pp. 5-12 ◽  
Author(s):  
E S Grigoryeva ◽  
D A Kokova ◽  
A N Gratchev ◽  
E S Cherdyntsev ◽  
M A Buldakov ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Lung Cancer ◽  
Dna Adducts ◽  
Early Stage ◽  
Threshold Concentration ◽  
Individual Characteristics ◽  
The Body ◽  
Mass Spectrometry Analysis ◽  
Lung Carcinogenesis ◽  
Spectrometry Analysis

In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high pathogenetic importance in the lung carcinogenesis and can be identified in biological samples with high accuracy and reliability using highly sensitive mass spectrometry methods (TOF/TOF, TOF/MS, MS/MS). The appearance of DNA adducts in blood or tissues is the result of the interaction of carcinogenic factors, such as tobacco constituents, and the body reaction which is determined by individual characteristics of metabolic and repair systems. So, DNA adducts may be considered as a cumulative mirror of heterogeneous response of different individuals to smoking carcinogens, which finally could determine the risk for lung cancer. This review is devoted to analysis of the role of DNA adducts in lung carcinogenesis in order to demonstrate their usefulness as cancer associated markers. Currently, there are some serious limitations impeding the widespread use of DNA adducts as cancer biomarkers, due to failure of standardization of mass spectrometry analysis in order to correctly measure the adduct level in each individual. However, it is known that all DNA adducts are immunogenic, their accumulation over some threshold concentration leads to the appearance of long-living autoantibodies. Thus, detection of an informative pattern of autoantibodies against DNA adducts using innovative multiplex ELISA immunoassay may be a promising approach to find lung cancer at an early stage in high-risk groups (smokers, manufacturing workers, urban dwellers).

scholarly journals De-ubiquitination of SAMHD1 by USP7 overcomes oncogenic stress and contributes to chemotherapy insensitivity

2021 ◽  
Author(s):  
Jingwei Liu ◽  
Tingting Zhou ◽  
xiang dong ◽  
Qiqiang Guo ◽  
Lixia Zheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Infections ◽  
Early Stage ◽  
Genotoxic Stress ◽  
Repair Process ◽  
Chemotherapeutic Agents ◽  
Human Carcinoma ◽  
Oncogenic Stress

Abstract Oncogenic stress induces DNA damage response (DDR) that guards against genetic instability during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression, and promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that targeting USP7 may help overcome chemoresistance, thus necessitating further investigation in the pursuit of precision medicine.

Spectrophotometry Measurement of Polynuclear Aromatic Hydrocarbons in Hamilton Harbour Sediments

1991 ◽  
Vol 26 (1) ◽  
pp. 1-16 ◽  
Author(s):  
T.P. Murphy ◽  
H. Brouwer ◽  
M.E. Fox ◽  
E. Nagy
Keyword(s):  
Aromatic Hydrocarbons ◽  
Total Concentration ◽  
Coal Tar ◽  
Sediment Cores ◽  
Polynuclear Aromatic Hydrocarbons ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Near Surface ◽  
Spectrometry Analysis ◽  
Hamilton Harbour

Abstract Eighty-one sediment cores were collected to determine the extent of coal tar contamination in a toxic area of Hamilton Harbour. Over 800 samples were analyzed by a UV spectrophotometric technique that was standardized with gas chromatography/mass spectrometry analysis. The coal tar distribution was variable. The highest concentrations were near the Stelco outfalls and the Hamilton-Wentworth combined sewer outfalls. The total concentration of the 16 polynuclear aromatic hydrocarbons (PAHs) in 48,300 m3 of near-surface sediments exceeded 200 µg/g.

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