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1
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Fold recognition insights into function of herpes ICP4 protein

100%
Wyrwicz L. S., Rychlewski L.
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2007
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vol. 54
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issue 3
551-559
EN
ICP4 is an important factor regulating the life cycle of HSV1. This conserved protein has several molecular functions, including activation of expression of viral late gene transcripts and inhibition of immediate early genes. Although ICP4 and its Alphaherpesvirinae homologs (eg.: IE62 of VZV) have been subjects of various molecular studies, a complete view of their molecular function is lacking. Here we present the results of fold recognition and molecular modelling of ICP4 functional domains. The performed state-of-the-art bioinformatic fold recognition analysis identified a dual helix-turn-helix motif as a binding module of repressor activities (so called region 2 domain). The mapping of distant homology identified that a segment responsible for activation of late gene promoters (region 4) exhibits folding of uracil DNA glycosylase (UDG), but seems to be a non-functional homolog of UDG. Potential implications of the results are discussed.
2
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Cytomegalovirus immediate early gene UL37 encodes a novel MHC-like protein

100%
Wyrwicz L. S., Rychlewski L.
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2008
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vol. 55
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issue 1
67-74
EN
The cytomegalovirus (CMV) genome encodes four clusters of genes expressed immediately after infection - i.e.: UL36-38, UL122-123, TRS1-IRS1, and US3. The general function of these genes is associated with inhibition of cellular mechanisms of antiviral response. Although several biological processes have been mapped onto specific gene products, the knowledge of the molecular mechanism of their activity remains fragmentary. Here, we report the application of protein structure prediction methods in assigning the function to a glycosylated domain encoded by UL37 of CMV (gpUL37, UL37x3). The discerned similarity clearly points out that this domain represents a novel type of a major histocompatibility complex (MHC)-like protein, and consequently may play a central role in an additional mechanism of escape from antiviral response.
3
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Homologues of HSV-1 nuclear egress factor UL34 are potential phosphoinositide-binding proteins

81%
Wyrwicz L. S., Koczyk G., Rychlewski L.
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2008
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vol. 55
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issue 1
207-213
EN
During the herpesvirus replication cycle, viral transcription, DNA replication, formation of capsids and DNA packaging occur in the nucleus. The subsequent nuclear egress of newly synthesized nucleocapsids is performed by budding of the inner leaflet of the nuclear membrane, which creates the primary envelope. Although products of two genes conserved throughout the Herpesviridae family (HSV-1 UL34 and UL31) have previously been shown to be involved in the execution of this process, the molecular basis of their activity is not clear. Here we present results of protein structure prediction for the conserved domain of UL34. The applied methodology suggests that this protein adopts a pleckstrin homology (PH) fold to perform its function. A detailed inspection of the ligand binding site strongly supports the hypothesis that UL34 orthologs can recognize phosphoinositides. Since previous works suggest that alterations of UL34 gene product result in a drastic impairment of primary envelopment of HSV-1 and trapping of capsids in the nucleus, the presented data may lead to the development of novel anti-herpetic therapeutic strategies where analogs of phosphoinositides are administered.
4
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Unexpected domain composition of MACC1 links MET signaling and apoptosis

81%
Kokoszyńska K., Kryński J., Rychlewski L., Wyrwicz L. S.
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issue 2
317-324
EN
Colorectal cancer, one of the most challenging malignancies, still has a limited number of recognized prognostic and predictive markers indicating appropriate treatment. MACC1 (metastasis-associated in colon cancer-1), a novel regulator of tumor growth and metastasis has recently been identified as an important prognostic factor of metastatic disease in colorectal cancer. The mechanism of MACC1 activity remains undetermined. Here we apply a combination of fold recognition and homology modeling algorithms to draft MACC1 function. The applied methods revealed that the MACC1 protein consists of four domains: ZU5, SH3, and two C-terminal death domains (DD). Previously a similar domain architecture (ZU5-DD) was observed in other proteins, involved mainly in signal transduction and apoptosis regulation. Based on the specific aspects of the closest homologues' biology functional hypotheses on MACC1 are proposed. A broad range of bioinformatic analyzes indicates that MACC1, besides its involvement in signal transduction from the MET receptor, links MET signaling and apoptosis.
5
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A common cis-element in promoters of protein synthesis and cell cycle genes

71%
Wyrwicz L. S., Gaj P., Hoffmann M., Rychlewski L., Ostrowski J.
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EN
Gene promoters contain several classes of functional sequence elements (cis elements) recognized by protein agents, e.g. transcription factors and essential components of the transcription machinery. Here we describe a common DNA regulatory element (tandem TCTCGCGAGA motif) of human TATA-less promoters. A combination of bioinformatic and experimental methodology suggests that the element can be critical for expression of genes involved in enhanced protein synthesis and the G1/S transition in the cell cycle. The motif was identified in a substantial fraction of promoters of cell cycle genes, like cyclins (CCNC, CCNG1), as well as transcription regulators (TAF7, TAF13, KLF7, NCOA2), chromatin structure modulators (HDAC2, TAF6L), translation initiation factors (EIF5, EIF2S1, EIF4G2, EIF3S8, EIF4) and previously reported 18 ribosomal protein genes. Since the motif can define a subset of promoters with a distinct mechanism of activation involved in regulation of expression of about 5% of human genes, further investigation of this regulatory element is an emerging task.
6
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Mitochondria-associated satellite I RNA binds to hnRNP K protein

61%
Klimek-Tomczak K., Mikula M., Dzwonek A., Paziewska A., Wyrwicz L. S., Hennig E. E., Ostrowski J.
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2006
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vol. 53
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issue 1
169-178
EN
hnRNP K protein, which localizes to the nucleus, cytoplasm and mitochondria, is involved in the various cellular processes that compose gene expression. We used a SAGE-based assay to profile RNAs associated with hnRNP K protein in rat mitochondria. RNA was isolated from mitoplasts obtained from highly purified and RNase-treated mitochondria. Total RNA and RNA associated with hnRNP K protein were then used as input material for generating two SAGE libraries. Mitochondrion-derived tags isolated from the total mitoplast RNA library represented 86.3%, while those isolated from the library constructed from RNA associated with hnRNP K protein represented only 28.2% of selected tags. Thus, an unexpected number of nuclear-encoded RNAs were purified from mitochondria. Many of these transcripts were co-purified with hnRNP K protein, and high levels of nuclear-encoded RNAs co-immunoprecipitating with K protein corresponded to elevated hnRNP K protein levels of the organelle. The most abundant RNAs that were co-purified with hnRNP K protein represented transcripts originating from satellite I DNA. While satellite I RNA levels were higher in the nucleus and cytoplasm than in mitochondria, the most abundant binding of satellite I transcripts to hnRNP K protein was found in mitochondria. The role of satellite I RNA in mitochondria remains to be elucidated.
7
Content available remote

Gene expression alterations induced by low molecular weight heparin during bowel anastomosis healing in rats

42%
Krześniak N., Paziewska A., Rubel T., Skrzypczak M., Mikula M., Dzwonek A., Goryca K., Wyrwicz L. S., Jarosz D., Laubitz D., Woszczyński M., Bielecki K., Ostrowski J.
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2011
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vol. 58
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issue 1
79-87
EN
Colon anastomosis is therapeutically challenging because multiple, usually undetectable factors influence a spectrum of repair mechanisms. We hypothesized that low molecular weight heparins, routinely administered perioperatively, may differentially affect gene expression related to colon healing. Twenty pairs of untreated and enoxaparin-treated rats underwent left-side hemicolectomy with a primary end-to-end anastomosis. Normal colon and anastomotic bowel segments were resected on day 0 and on days 1, 3, 5, and 7 after surgery, respectively. Serial anastomosis transverse cross-sections were evaluated microscopically and by microarray (Rat Genome 230 2.0, Affymetrix). Differentially expressed probe sets were annotated with Gene Ontology. We also examined the influence of enoxaparin on fibroblast proliferation and viability in vitro. Among the 5476 probe sets, we identified differential expression at each healing time point, yielding 79 subcategories. Most indicated genes were involved in wound healing, including multicellular organismal development, locomotory behavior, immune response, cell adhesion, inflammatory response, cell-cell signaling, blood vessel development, and tissue remodeling. Although we found no intensity differences in histological features of healing between enoxaparin-treated and control rats, treatment did induce significant expression changes during early healing. Of these changes, 83 probe sets exhibited at least twofold changes and represented different functional annotations, including inflammatory response, regulation of transcription, regulation of apoptosis, and angiogenesis. Fibroblast culture confirmed an anti-viability effect of enoxaparin. Enoxaparin affects colon wound-related gene expression profiles, but further studies will resolve whether heparin treatment is a risk factor after intestinal surgery, at least in some patients.
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