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11.
hRAD51 lacks cooperative DNA-dependent ATPase activity and appears to function with 5-10-fold less Mg2+ compared to RecA. We have further explored the effect of Mg2+ on adenosine nucleotide binding, ATPase, and DNA strand exchange activities. hRAD51 was saturated with the poorly hydrolyzable analog of ATP, ATPgammaS, at approximately 0.08 mM Mg2+. In contrast, > 0.5 mM Mg2+ was required to saturate hRAD51 with ADP. We found ADP to be a significantly less effective competitive inhibitor of the hRAD51 ATPase at low Mg2+ concentrations (0.08 mM). Mg2+ did not appear to affect the ability of ATPgammaS to competitively inhibit the hRAD51 ATPase. Low Mg2+ (0.08-0.12 mM) enhanced the steady-state ATPase of hRAD51 while higher Mg2+ concentration (> 0.3 mM) was inhibitory. At low Mg2+, hRAD51 appeared capable of nearly complete hydrolysis of available ATP, suggesting a lack of ADP product inhibition. There was a strong correlation between the amount of Mg2+ required for stable ADP binding and the inhibition of hRad51 strand exchange activity. Simultaneous inclusion of exogenous ATP and chelation of Mg2+ with EDTA significantly enhanced ADP-->ATP exchange by hRAD51. These studies are consistent with the hypothesis that Mg2+ influences the discrimination and release of ADP, which may sequentially impose an important regulatory step in the hRAD51 ATPase cycle. 相似文献
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Tomas ML Eagan Esteban C Gabazza Corina D’Alessandro-Gabazza Paloma Gil-Bernabe Shinya Aoki Jon A Hardie Per S Bakke Peter D Wagner 《Respiratory research》2012,13(1):48
Background
Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years.Methods
The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models.Results
At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry.Conclusion
This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients. 相似文献14.
Signaling mismatch repair in cancer. 总被引:5,自引:0,他引:5
R Fishel 《Nature medicine》1999,5(11):1239-1241
Clinical diagnosis of mismatch repair defects has recently been complicated by the discovery of multiple gene alterations that lead to an expanded tumor spectrum. Studies of mismatch repair protein function will improve our understanding of this process and result in better prognostic indicators of mismatch repair-associated tumor development. 相似文献
15.
Large, rapidly evolving intergenic spacers in the mitochondrial DNA of the salamander family Ambystomatidae (Amphibia: Caudata) 总被引:5,自引:2,他引:3
We report the presence, in the mitochondrial DNA (mtDNA) of all of the
sexual species of the salamander family Ambystomatidae, of a shared 240- bp
intergenic spacer between tRNAThr and tRNAPro. We place the intergenic
spacer in context by presenting the sequence of 1,746 bp of mtDNA from
Ambystoma tigrinum tigrinum, describe the nucleotide composition of the
intergenic spacer in all of the species of Ambystomatidae, and compare it
to other coding and noncoding regions of Ambystoma and several other
vertebrate mtDNAs. The nucleotide substitution rate of the intergenic
spacer is approximately three times faster than the substitution rate of
the control region, as shown by comparisons among six Ambystoma
macrodactylum sequences and eight members of the Ambystoma tigrinum
complex. We also found additional inserts within the intergenic spacers of
five species that varied from 87-444 bp in length. The presence of the
intergenic spacer in all sexual species of Ambystomatidae suggests that it
arose at least 20 MYA and has been a stable component of the ambystomatid
mtDNA ever since. As such, it represents one of the few examples of a large
and persistent intergenic spacer in the mtDNA of any vertebrate clade.
相似文献
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Jingxin Wang Naduparambil K Jacob Katherine J Ladner Amer Beg James D Perko Stephan M Tanner Sandya Liyanarachchi Richard Fishel Denis C Guttridge 《EMBO reports》2009,10(11):1272-1278
Nuclear factor (NF)-κB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF-κB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65−/− murine fibroblasts immortalize at considerably faster rates than RelA/p65+/+ cells. The ability of RelA/p65−/− fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65−/− fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF-κB. Altogether, our findings present a fresh perspective on the role of NF-κB as a tumour suppressor, which acts in pre-neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability. 相似文献
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Heinen CD Cyr JL Cook C Punja N Sakato M Forties RA Lopez JM Hingorani MM Fishel R 《The Journal of biological chemistry》2011,286(46):40287-40295
The mechanics of hMSH2-hMSH6 ATP binding and hydrolysis are critical to several proposed mechanisms for mismatch repair (MMR), which in turn rely on the detailed coordination of ATP processing between the individual hMSH2 and hMSH6 subunits. Here we show that hMSH2-hMSH6 is strictly controlled by hMSH2 and magnesium in a complex with ADP (hMSH2(magnesium-ADP)-hMSH6). Destabilization of magnesium results in ADP release from hMSH2 that allows high affinity ATP binding by hMSH6, which then enhances ATP binding by hMSH2. Both subunits must be ATP-bound to efficiently form a stable hMSH2-hMSH6 hydrolysis-independent sliding clamp required for MMR. In the presence of magnesium, the ATP-bound sliding clamps remain on the DNA for ~8 min. These results suggest a precise stepwise kinetic mechanism for hMSH2-hMSH6 functions that appears to mimic G protein switches, severely constrains models for MMR, and may partially explain the MSH2 allele frequency in Lynch syndrome or hereditary nonpolyposis colorectal cancer. 相似文献