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11.
VLJ Whitehall TD Dumenil DM McKeone CE Bond ML Bettington RL Buttenshaw L Bowdler GW Montgomery LF Wockner BA Leggett 《Epigenetics》2014,9(11):1454-1460
The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features. 相似文献
12.
The small-subunit ribosomal RNA gene sequences from the hypotrichous ciliates Oxytricha nova and Stylonychia pustulata 总被引:17,自引:0,他引:17
We have determined the complete nucleotide sequence of the small- subunit
ribosomal RNA genes for the ciliate protozoans Stylonychia pustulata and
Oxytricha nova. The sequences are homologous and sufficiently similar that
these organisms must be closely related. In a phylogeny inferred from
comparisons of several eukaryotic small-subunit ribosomal RNAs, the
divergence of the ciliates from the eukaryotic line of descent is seen to
coincide with the radiation of the plants, the animals, and the fungi. This
radiation is preceded by the divergence of the slime mold, Dictyostelium
discoideum.
相似文献
13.
Molecular population genetics of ref(2)P, a locus which confers viral resistance in Drosophila 总被引:4,自引:0,他引:4
The ref(2)P locus (2-54.2) is polymorphic for two allelic forms in natural
populations of Drosophila melanogaster, ref(2)Po and ref(2)Pp. The latter
allele confers resistance to the rhabdovirus sigma infecting wild
populations. Previous work, based on a small sample of prescreened
restrictive (resistant) and permissive (susceptible) alleles, identified a
large number of amino acid replacement changes (7) relative to synonymous
changes (1). Such protein variability could be the result of
variation-enhancing selection. To further test the selection hypothesis, we
have examined the DNA sequences of ten randomly chosen lines of D.
melanogaster and one line of D. simulans. Nine of the ten lines are
permissive; D. simulans does not harbor the virus. The melanogaster alleles
contain 4 synonymous changes, 19 noncoding changes, and 13 amino acid
replacement changes, indicating a relatively high level of polymorphism.
Three sequenced restrictive alleles have nearly identical sequences,
indicating that they are relatively young. Compared to the permissive
alleles, they share only a complex deletion at codon 34, CAG-AAT to GGA,
which our analysis indicates to be the site conferring the restrictive
phenotype. Patterns of polymorphism and divergence differ from neutral
predictions by several criteria for the amino terminal region, which
contains the complex deletion (codons 1-91), but not the remainder of the
protein (codons 92-599). We find a higher rate of evolution on the D.
melanogaster lineage than on the D. simulans lineage. The relatively large
amount of both replacement and silent polymorphism in the permissive
alleles and the lack of divergence between permissive and restrictive
alleles suggests that the sigma virus and ref(2)P may be engaged in an
evolutionary race in which new restrictive alleles are continually arising
but are relatively short-lived.
相似文献
14.
Relationships among msx gene structure and function in zebrafish and other vertebrates 总被引:6,自引:2,他引:4
Ekker M; Akimenko MA; Allende ML; Smith R; Drouin G; Langille RM; Weinberg ES; Westerfield M 《Molecular biology and evolution》1997,14(10):1008-1022
The zebrafish genome contains at least five msx homeobox genes, msxA, msxB,
msxC, msxD, and the newly isolated msxE. Although these genes share
structural features common to all Msx genes, phylogenetic analyses of
protein sequences indicate that the msx genes from zebrafish are not
orthologous to the Msx1 and Msx2 genes of mammals, birds, and amphibians.
The zebrafish msxB and msxC are more closely related to each other and to
the mouse Msx3. Similarly, although the combinatorial expression of the
zebrafish msx genes in the embryonic dorsal neuroectoderm, visceral arches,
fins, and sensory organs suggests functional similarities with the Msx
genes of other vertebrates, differences in the expression patterns preclude
precise assignment of orthological relationships. Distinct duplication
events may have given rise to the msx genes of modern fish and other
vertebrate lineages whereas many aspects of msx gene functions during
embryonic development have been preserved.
相似文献
15.
The MMS22L–TONSL heterodimer directly promotes RAD51‐dependent recombination upon replication stress
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Wojciech Piwko Karun Mutreja Lepakshi Ranjha Diana Stafa Alexander Smirnov Mia ML Brodersen Ralph Zellweger Andreas Sturzenegger Pavel Janscak Massimo Lopes Matthias Peter Petr Cejka 《The EMBO journal》2016,35(23):2584-2601
Homologous recombination (HR) is a key pathway that repairs DNA double‐strand breaks (DSBs) and helps to restart stalled or collapsed replication forks. How HR supports replication upon genotoxic stress is not understood. Using in vivo and in vitro approaches, we show that the MMS22L–TONSL heterodimer localizes to replication forks under unperturbed conditions and its recruitment is increased during replication stress in human cells. MMS22L–TONSL associates with replication protein A (RPA)‐coated ssDNA, and the MMS22L subunit directly interacts with the strand exchange protein RAD51. MMS22L is required for proper RAD51 assembly at DNA damage sites in vivo, and HR‐mediated repair of stalled forks is abrogated in cells expressing a MMS22L mutant deficient in RAD51 interaction. Similar to the recombination mediator BRCA2, recombinant MMS22L–TONSL limits the assembly of RAD51 on dsDNA, which stimulates RAD51‐ssDNA nucleoprotein filament formation and RAD51‐dependent strand exchange activity in vitro. Thus, by specifically regulating RAD51 activity at uncoupled replication forks, MMS22L–TONSL stabilizes perturbed replication forks by promoting replication fork reversal and stimulating their HR‐mediated restart in vivo. 相似文献
16.
Effects of EDTA treatment upon the protein subunit composition and mechanical properties of mammalian single skeletal muscle fibers 总被引:9,自引:0,他引:9
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Considerable interest has been focused on the role of myosin light chain LC(2) in the contraction of vertebrate striated muscle. A study was undertaken to further our investigations (Moss, R.L., G.G. Giulian, and M.L. Greaser, 1981, J. Biol. Chem., 257:8588-8591) of the effects of LC(2) removal upon contraction in skinned fibers from rabbit psoas muscles. Isometric tension and maximum velocity of shortening, V(max), were measured in fiber segments prior to LC(2) removal. The segments were then bathed at 30 degrees C for up to 240 min in a buffer solution containing 20 mM EDTA in order to extract up to 60 percent of the LC(2). Troponin C (TnC) was also partially removed by this procedure. Mechanical measurements were done following the EDTA extraction and the readditions of first TnC and then LC(2) to the segments. The protein subunit compositions of the same fiber segments were determined following each of these procedures by SDS PAGE of small pieces of the fiber. V(max) was found to decrease as the LC(2) content of the fiber segments was reduced by increasing the duration of extraction. EDTA treatment also resulted in substantial reductions in tension due mainly to the loss of TnC, though smaller reductions due to the extraction of LC(2) were also observed. Reversal of the order of recombination of LC(2) and TnC indicated that the reduction in V(max) following EDTA treatment was a specific effect of LC(2) removal. These results strongly suggest that LC(2) may have roles in determining the kinetics and extent of interaction between myosin and actin. 相似文献
17.
Nucleotide sequence analysis of the lemur beta-globin gene family: evidence for major rate fluctuations in globin polypeptide evolution 总被引:1,自引:0,他引:1
Lemur beta-related globin genes have been isolated and sequenced. Orthology
of prosimian and human epsilon-, gamma-, and beta-related globin genes was
established by dot-matrix analysis. All of these lemur globin genes
potentially encode functional beta-related globin polypeptides, though
precisely when the gamma-globin gene is expressed remains unknown. The
organization of the 18-kb brown lemur beta-globin gene cluster (5'
epsilon-gamma-[psi eta-delta]-beta 3') is consistent with its evolution by
contraction via unequal crossing-over from the putative ancestral mammalian
beta-globin gene cluster (5' epsilon-gamma- eta-delta-beta 3'). The dwarf
lemur nonadult globin genes are arranged as in the brown lemur. Similar
levels of synonymous (silent) nucleotide substitutions and noncoding DNA
sequence differences have accumulated between species in all of these
genes, suggesting a uniform rate of noncoding DNA divergence throughout
primate beta-globin gene clusters. These differences are comparable with
those observed in the nonfunctional psi eta pseudogene and have therefore
accumulated at the presumably maximal neutral rate. In contrast,
nonsynonymous (replacement) nucleotide substitutions show a significant
heterogeneity in distribution for both the same gene in different lineages
and different genes in the same lineage. These major fluctuations in
replacement but not silent substitution rates cannot be attributed to
changes in mutation rate, suggesting that changes in the rate of globin
polypeptide evolution in primates is not governed solely by variable
mutation rates.
相似文献
18.
Chromatography on DEAE-cellulose of an extract from etiolated leaves of sorghum ( Sorghum vulgare Pers. cv. INRA 450), a C4 plant, gave only one form of phosphoenol pyruvate carboxylase with functional and regulatory properties of a C3 type plant enzyme. Greening of the leaves resulted in a significant increase in activity. This increase was due to the appearance of a new form of the enzyme, which eluted at lower ionic strength and exhibited new properties. This form was glucose-6-P activated and showed a sigmoidal curve response to the concentration of the substrate phosphoerralpyruvate. These kinetic properties are typical of a C4 plant enzyme. 相似文献
19.
Voltage-sensitive and solvent-sensitive processes in ion channel gating. Kinetic effects of hyperosmolar media on activation and deactivation of sodium channels.
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Kinetic effects of osmotic stress on sodium ionic and gating currents have been studied in crayfish giant axons after removal of fast inactivation with chloramine-T. Internal perfusion with media made hyperosmolar by addition of formamide or sucrose, reduces peak sodium current (before and after removal of fast inactivation with chloramine-T), increases the half-time for activation, but has no effect on tail current deactivation rate(s). Kinetics of ON and OFF gating currents are not affected by osmotic stress. These results confirm (and extend to sodium channels) the separation of channel gating mechanisms into voltage-sensitive and solvent-sensitive processes recently proposed by Zimmerberg J., F. Bezanilla, and V. A. Parsegian. (1990. Biophys. J. 57:1049-1064) for potassium delayed rectifier channels. Additionally, the kinetic effects produced by hyperosmolar media seem qualitatively similar to the kinetic effects of heavy water substitution in crayfish axons (Alicata, D. A., M. D. Rayner, and J. G. Starkus. 1990. Biophys. J. 57:745-758). However, our observations are incompatible with models in which voltage-sensitive and solvent-sensitive gating processes are presumed to be either (a) strictly sequential or, (b) parallel and independent. We introduce a variant of the parallel model which includes explicit coupling between voltage-sensitive and solvent-sensitive processes. Simulations of this model, in which the total coupling energy is as small as 1/10th of kT, demonstrate the characteristic kinetic changes noted in our data. 相似文献
20.