| 1. |
- Balonova, Lucie, et al.
(author)
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Characterization of protein glycosylation in Francisella tularensis subsp holarctica
- 2012
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In: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 11:7
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Journal article (peer-reviewed)abstract
- FTH_0069 is a previously uncharacterized strongly immunoreactive protein that has been proposed to be a novel virulence factor in Francisella tularensis. Here, the glycan structure modifying two C-terminal peptides of FTH_0069 was identified utilizing high resolution, high mass accuracy mass spectrometry, combined with in-source CID tandem MS experiments. The glycan observed at m/z 1156 was determined to be a hexasaccharide, consisting of two hexoses, three N-acetylhexosamines, and an unknown monosaccharide containing a phosphate group. The monosaccharide sequence of the glycan is tentatively proposed as X-P-HexNAc-HexNAc-Hex-Hex-HexNAc, where X denotes the unknown monosaccharide. The glycan is identical to that of DsbA glycoprotein, as well as to one of the multiple glycan structures modifying the type IV pilin PilA, suggesting a common biosynthetic pathway for the protein modification. Here, we demonstrate that the glycosylation of FTH_0069, DsbA, and PilA was affected in an isogenic mutant with a disrupted wbtDEF gene cluster encoding O-antigen synthesis and in a mutant with a deleted pglA gene encoding pilin oligosaccharyltransferase PglA. Based on our findings, we propose that PglA is involved in both pilin and general F. tularensis protein glycosylation, and we further suggest an inter-relationship between the O-antigen and the glycan synthesis in the early steps in their biosynthetic pathways. Molecular & Cellular Proteomics 11: 10.1074/mcp.M111.015016, 1-12, 2012.
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| 2. |
- Bartkova, Jirina, et al.
(author)
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Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer : MRE11 as a candidate familial cancer-predisposing gene
- 2008
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In: Molecular Oncology. - : Wiley. - 1574-7891. ; 2:4, s. 296-316
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Journal article (peer-reviewed)abstract
- The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11-RAD50-NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (gamma H2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.
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| 3. |
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| 4. |
- Fagerholm, Rainer, et al.
(author)
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NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer
- 2008
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:7, s. 844-53
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Journal article (peer-reviewed)abstract
- NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.
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| 5. |
- Groth, Anja, et al.
(author)
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Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint
- 2003
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In: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 22:7, s. 1676-1687
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Journal article (peer-reviewed)abstract
- All eukaryotes respond to DNA damage by modulation of diverse cellular processes to preserve genomic integrity and ensure survival. Here we identify mammalian Tousled like kinases (Tlks) as a novel target of the DNA damage checkpoint. During S-phase progression, when Tlks are maximally active, generation of DNA double-strand breaks (DSBs) leads to rapid and transient inhibition of Tlk activity. Experiments with chemical inhibitors, genetic models and gene targeting through RNA interference demonstrate that this response to DSBs requires ATM and Chk1 function. Chk1 phosphorylates Tlk1 on serine 695 (S695) in vitro, and this UCN-01- and caffeine-sensitive site is phosphorylated in vivo in response to DNA damage. Substitution of S695 to alanine impaired efficient downregulation of Tlk1 after DNA damage. These findings identify an unprecedented functional co- operation between ATM and Chk1 in propagation of a checkpoint response during S phase and suggest that, through transient inhibition of Tlk kinases, the ATM-Chk1-Tlk pathway may regulate processes involved in chromatin assembly.
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| 6. |
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| 7. |
- Storgaard Sørensen, Claus, et al.
(author)
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Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.
- 2003
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In: Cancer Cell. - 1535-6108. ; 3:3, s. 247-58
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Journal article (peer-reviewed)abstract
- Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS). The basal turnover of Cdc25A operating in unperturbed S phase required Chk1-dependent phosphorylation of serines 123, 178, 278, and 292. IR-induced acceleration of Cdc25A proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of Chk1 and Chk2 kinases. Finally, phosphorylation of Chk1 by ATM was required to fully accelerate the IR-induced degradation of Cdc25A. Our results provide evidence that the mammalian S phase checkpoint functions via amplification of physiologically operating, Chk1-dependent mechanisms.
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| 8. |
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| 9. |
- Bábek, Ondřej, et al.
(author)
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Redox geochemistry of the red ‘orthoceratite limestone’ of Baltoscandia : Possible linkage to mid-Ordovician palaeoceanographic changes
- 2021
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In: Sedimentary Geology. - : Elsevier BV. - 0037-0738. ; 420
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Journal article (peer-reviewed)abstract
- The orthoceratite limestone of the Ordovician epicontinental sea of Baltoscandia is one of the oldest Phanerozoic examples of pelagic marine red beds (MRBs). Being enriched in authigenic haematite, MRBs are considered to be sensitive palaeoceanographic redox indicators. In this paper, the origin of the reddening of the Ordovician MRBs and its timing and redox conditions were addressed at two sections, and in a drill core in the Kinnekulle area, Sweden, through the application of diffuse reflectance spectroscopy, sedimentary petrology (microfacies and electron microprobe), bulk-rock and in-situ element geochemistry (laser-ablation ICP-MS) and molybdenum stable isotope systematics. Enrichment in haematite (up to ~0.05 wt%) occurred during very early diagenesis under low sedimentation rates (~5 mm/kyr), which is comparable to several examples of Phanerozoic MRBs. The reddening was associated with the mm-scale, in-situ mobility of Fe, Mn, As, Mo and U, due to Fe–Mn redox cycling between primary and secondary minerals and pore water under oxic and suboxic to anoxic conditions; it was not related to significant changes in seawater chemistry. Stratigraphic red-to-grey transitions likely coincided with two mid-Darriwilian global regressions (the so-called Täljsten and at the base of the Gullhögen Formation), likely due to the effects of changing sedimentation rates and sub-bottom redox potentials. The Ordovician MRBs coincided with a positive δ13C excursion during the middle Darriwilian, which is different to MRB examples cited from the Devonian to the Cretaceous age, which frequently coincide with shifts to lower values of δ13C. Although MRBs are believed to show a time-specific occurrence in greenhouse or transitional greenhouse-to-icehouse climatic modes by several authors, our study suggests that causal links between MRBs and global carbon cycle remain unclear.
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| 10. |
- Cerveny, Lukas, et al.
(author)
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Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens : Role in Virulence Mechanisms
- 2013
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In: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 81:3, s. 629-635
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Research review (peer-reviewed)abstract
- The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while high-lighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of Yersinia, Pseudomonas, and Shigella.
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