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991.
In Saccharomyces cerevisiae, the Mre11/Rad50/Xrs2 (MRX) complex plays important roles in both homologous and non-homologous pathways of DNA repair. In this study, we investigated the role of the MRX complex and its enzymatic functions in non-homologous repair of DNA ends containing incompatible end structures. Using a plasmid transformation assay, we found that mre11 and rad50 null strains are extremely deficient in joining of incompatible DNA ends. Expression of the nuclease-deficient Mre11 mutant H125N fully complemented the mre11 strain for joining of mismatched ends in the absence of homology, while a mutant of Rad50 deficient in ATP-dependent activities exhibited levels of end-joining similar to a rad50 deletion strain. Although the majority of non-homologous end-joining (NHEJ) products isolated did not contain microhomologies, introduction of an 8bp microhomology at mismatched ends resulted in microhomology-mediated joining in all of the products recovered, demonstrating that a microhomology exerts a dominant effect on processing events that occur during NHEJ. Nuclease-deficient Mre11p was less efficient in promoting microhomology-mediated end-joining in comparison to its ability to stimulate non-microhomology-mediated events, suggesting that Mre11p influences, but is not essential for, microhomology-mediated repair. When the linearized DNA was transformed in the presence of an intact homologous plasmid to facilitate gap repair, there was no decrease in NHEJ products obtained, suggesting that NHEJ and homologous repair do not compete for DNA ends in vivo. These results suggest that the MRX complex is essential for joining of incompatible ends by NHEJ, and the ATP-dependent activities of Rad50 are critical for this process. 相似文献
992.
Somatic mutations have a role in the pathogenesis of a number of diseases, particularly cancers. Here we present data supporting
a role of mitochondrial somatic mutations in an autoimmune disease, rheumatoid arthritis (RA). RA is a complex, multifactorial
disease with a number of predisposition traits, including major histocompatibility complex (MHC) type and early bacterial
infection in the joint. Somatic mutations in mitochondrial peptides displayed by MHCs may be recognized as non-self, furthering
the destructive immune infiltration of the RA joint. Because many bacterial proteins have mitochondrial homologues, the immune
system may be primed against these altered peptides if they mimic bacterial homologues. In addition, somatic mutations may
be influencing cellular function, aiding in the acquirement of transformed properties of RA synoviocytes. To test the hypothesis
that mutations in mitochondrial DNA (mtDNA) are associated with RA, we focused on the MT-ND1 gene for mitochondrially encoded NADH dehydrogenase 1 (subunit one of complex I – NADH dehydrogenase) of synoviocyte mitochondria
from RA patients, using tissue from osteoarthritis (OA) patients for controls. We identified the mutational burden and amino
acid changes in potential epitope regions in the two patient groups. RA synoviocyte mtDNA had about twice the number of mutations
as the OA group. Furthermore, some of these changes had resulted in potential non-self MHC peptide epitopes. These results
provide evidence for a new role for somatic mutations in mtDNA in RA and predict a role in other diseases. 相似文献
993.
994.
Ye Z Guo L Barakat KJ Pollard PG Palucki BL Sebhat IK Bakshi RK Tang R Kalyani RN Vongs A Chen AS Chen HY Rosenblum CI MacNeil T Weinberg DH Peng Q Tamvakopoulos C Miller RR Stearns RA Cashen DE Martin WJ Metzger JM Strack AM MacIntyre DE Van der Ploeg LH Patchett AA Wyvratt MJ Nargund RP 《Bioorganic & medicinal chemistry letters》2005,15(15):3501-3505
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents. 相似文献
995.
Ujjainwalla F Warner D Snedden C Grisson RD Walsh TF Wyvratt MJ Kalyani RN Macneil T Tang R Weinberg DH Van der Ploeg L Goulet MT 《Bioorganic & medicinal chemistry letters》2005,15(18):4023-4028
Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed. 相似文献
996.
Heightman TD Gaster LM Pardoe SL Pilleux JP Hadley MS Middlemiss DN Price GW Roberts C Scott CM Watson JM Gordon LJ Holland VA Powles J Riley GJ Stean TO Trail BK Upton N Austin NE Ayrton AD Coleman T Cutler L 《Bioorganic & medicinal chemistry letters》2005,15(19):4370-4374
The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies. 相似文献
997.
Flounders offer unique opportunities to study the cytological basis of vertebrate pigmentation. Individual skin pigment cells are clearly visible at hatching, and flounder ontogeny includes a dramatic shift in overall pigmentation (from symmetrical to asymmetrical) during metamorphosis. Moreover, several types of malpigmentation occur in hatchery populations; although much effort has gone into reducing the frequency of such defects, their etiology remains poorly understood, and they have rarely been described at the cellular level. In this paper, we use light and fluorescence microscopy to describe the cytological basis of normal developmental changes and of common types of malpigmentation. We then discuss the implications of these observations for underlying patterning mechanisms. 相似文献
998.
The centrosome is an indispensable component of the cell-cycle machinery of eukaryotic cells, and the perturbation of core centrosomal or centrosome-associated proteins is linked to cell-cycle misregulation and cancer. Recent work has expanded our understanding of the functional complexity and importance of this organelle. The centrosomal localization of proteins that are involved in human genetic disease, and the identification of novel centrosome-associated proteins, has shown that numerous, seemingly unrelated, cellular processes can be perturbed by centrosomal dysfunction. Here, we review the mechanistic relationship between human disease phenotypes and the function of the centrosome, and describe some of the newly-appreciated functions of this organelle in animal cells. 相似文献
999.
Organic acids are valuable platform chemicals for future biorefining applications. Such applications involve the conversion
of low-cost renewable resources to platform sugars, which are then converted to platform chemicals by fermentation and further
derivatized to large-volume chemicals through conventional catalytic routes. Organic acids are toxic to many of the microorganisms,
such as Escherichia coli, proposed to serve as biorefining platform hosts at concentrations well below what is required for economical production.
The toxicity is two-fold including not only pH based growth inhibition but also anion-specific effects on metabolism that
also affect growth. E. coli maintain viability at very low pH through several different tolerance mechanisms including but not limited to the use of
decarboxylation reactions that consume protons, ion transporters that remove protons, increased expression of known stress
genes, and changing membrane composition. The focus of this mini-review is on organic acid toxicity and associated tolerance
mechanisms as well as several examples of successful organic acid production processes for E. coli. 相似文献
1000.
Mutations in the CCGTTCACA DnaA box of Mycobacterium tuberculosis oriC that abolish replication of oriC plasmids are tolerated on the chromosome
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Dziadek J Rajagopalan M Parish T Kurepina N Greendyke R Kreiswirth BN Madiraju MV 《Journal of bacteriology》2002,184(14):3848-3855
The origin of replication (oriC) region in some clinical strains of Mycobacterium tuberculosis is a hot spot for IS6110 elements. To understand how clinical strains with insertions in oriC can replicate their DNA, we characterized the oriC regions of some clinical strains. Using a plasmid-based oriC-dependent replication assay, we showed that IS6110 insertions that disrupted the DnaA box sequence CCGTTCACA abolished oriC activity in M. tuberculosis. Furthermore, by using a surface plasmon resonance technique we showed that purified M. tuberculosis DnaA protein binds native but not mutant DnaA box sequence, suggesting that stable interactions of the DnaA protein with the CCGTTCACA DnaA box are crucial for replication of oriC plasmids in vivo. Replacement by homologous recombination of the CCGTTCACA DnaA box sequence of the laboratory strain M. tuberculosis H37Ra with a mutant sequence did not result in nonviability. Together, these results suggest that M. tuberculosis strains have evolved mechanisms to tolerate mutations in the oriC region and that functional requirements for M. tuberculosis oriC replication are different for chromosomes and plasmids. 相似文献