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51.
FANCJ/BRIP1 encodes a helicase that has been implicated in the maintenance of genomic stability. Here, to better understand
FANCJ function in DNA damage responses, we have examined the regulation of its cellular localization. FANCJ nuclear foci assemble
spontaneously during S phase and are induced by various stresses. FANCJ foci colocalize with the replication fork following
treatment with hydroxyurea, but not spontaneously. Using FANCJ mutants, we find that FANCJ helicase activity and the capacity
to bind BRCA1 are both involved in FANCJ recruitment. Given similarities to the recruitment of another Fanconi anemia protein,
FANCD2, we tested for colocalization of FANCJ and FANCD2. Importantly, these proteins show substantial colocalization, and
FANCJ promotes the assembly of FANCD2 nuclear foci. This process is linked to the proper localization of FANCJ itself since
both FANCJ and FANCD2 nuclear foci are compromised by FANCJ mutants that abrogate its helicase activity or interaction with
BRCA1. Our results suggest that FANCJ is recruited in response to replication stress and that FANCJ/BRIP1 may serve to link
FANCD2 to BRCA1. 相似文献
52.
Transmitter molecules bind to synaptic acetylcholine receptor channels (AChRs) to promote a global channel-opening conformational change. Although the detailed mechanism that links ligand binding and channel gating is uncertain, the energy changes caused by mutations appear to be more symmetrical between subunits in the transmembrane domain compared with the extracellular domain. The only covalent connection between these domains is the pre-M1 linker, a stretch of five amino acids that joins strand β10 with the M1 helix. In each subunit, this linker has a central Arg (Arg3′), which only in the non-α-subunits is flanked by positively charged residues. Previous studies showed that mutations of Arg3′ in the α-subunit alter the gating equilibrium constant and reduce channel expression. We recorded single-channel currents and estimated the gating rate and equilibrium constants of adult mouse AChRs with mutations at the pre-M1 linker and the nearby residue Glu45 in non-α-subunits. In all subunits, mutations of Arg3′ had similar effects as in the α-subunit. In the ϵ-subunit, mutations of the flanking residues and Glu45 had only small effects, and there was no energy coupling between ϵGlu45 and ϵArg3′. The non-α-subunit Arg3′ residues had Φ-values that were similar to those for the α-subunit. The results suggest that there is a general symmetry between the AChR subunits during gating isomerization in this linker and that the central Arg is involved in expression more so than gating. The energy transfer through the AChR during gating appears to mainly involve Glu45, but only in the α-subunits. 相似文献
53.
Unique among primates, the colobine monkeys have adapted to a predominantly leaf-eating diet by evolving a foregut that utilizes bacterial fermentation to breakdown and absorb nutrients from such a food source. It has been hypothesized that pancreatic ribonuclease (pRNase) has been recruited to perform a role as a digestive enzyme in foregut fermenters, such as artiodactyl ruminants and the colobines. We present molecular analyses of 23 pRNase gene sequences generated from 8 primate taxa, including 2 African and 2 Asian colobine species. The pRNase gene is single copy in all noncolobine primate species assayed but has duplicated more than once in both the African and Asian colobine monkeys. Phylogenetic reconstructions show that the pRNase-coding and noncoding regions are under different evolutionary constraints, with high levels of concerted evolution among gene duplicates occurring predominantly in the noncoding regions. Our data suggest that 2 functionally distinct pRNases have been selected for in the colobine monkeys, with one group adapting to the role of a digestive enzyme by evolving at an increased rate with loss of positive charge, namely arginine residues. Conclusions relating our data to general hypotheses of evolution following gene duplication are discussed. 相似文献
54.
Yeast-based functional genomics and proteomics technologies: the first 15 years and beyond 总被引:1,自引:0,他引:1
Yeast-based functional genomics and proteomics technologies developed over the past decade have contributed greatly to our understanding of bacterial, yeast, fly, worm, and human gene functions. In this review, we highlight some of these yeast-based functional genomic and proteomic technologies that are advancing the utility of yeast as a model organism in molecular biology and speculate on their future uses. Such technologies include use of the yeast deletion strain collection, large-scale determination of protein localization in vivo, synthetic genetic array analysis, variations of the yeast two-hybrid system, protein microarrays, and tandem affinity purification (TAP)-tagging approaches. The integration of these advances with established technologies is invaluable in the drive toward a comprehensive understanding of protein structure and function in the cellular milieu. 相似文献
55.
Mostoslavsky R Chua KF Lombard DB Pang WW Fischer MR Gellon L Liu P Mostoslavsky G Franco S Murphy MM Mills KD Patel P Hsu JT Hong AL Ford E Cheng HL Kennedy C Nunez N Bronson R Frendewey D Auerbach W Valenzuela D Karow M Hottiger MO Hursting S Barrett JC Guarente L Mulligan R Demple B Yancopoulos GD Alt FW 《Cell》2006,124(2):315-329
The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes. 相似文献
56.
The melatonin rhythm generating system: developmental aspects 总被引:2,自引:0,他引:2
Development of the melatonin rhythm generating system, including the suprachiasmatic nucleus, sympathetic innervation, and biochemistry of the pineal gland is reviewed. This system offers investigators an interesting opportunity to study the effects of drugs, hormones, and other factors on the developmental appearance of specific structures and biochemical parameters, and to determine the role, if any, each has in the development of an integrated neural system. 相似文献
57.
58.
Chromatin-remodeling enzymes play essential roles in many biological processes, including gene expression, DNA replication and repair, and cell division. Although one such complex, SWI/SNF, has been extensively studied, new discoveries are still being made. Here, we review SWI/SNF biochemistry; highlight recent genomic and proteomic advances; and address the role of SWI/SNF in human diseases, including cancer and viral infections. These studies have greatly increased our understanding of complex nuclear processes. 相似文献
59.
Nicotinic acetylcholine receptor (AChR) channels at neuromuscular synapses rarely open in the absence of agonists, but many different mutations increase the unliganded gating equilibrium constant (E0) to generate AChRs that are active constitutively. We measured E0 for two different sets of mutant combinations and by extrapolation estimated E0 for wild-type AChRs. The estimates were 7.6 and 7.8×10(-7) in adult-type mouse AChRs (-100 mV at 23°C). The values are in excellent agreement with one obtained previously by using a completely different method (6.5×10(-7), from monoliganded gating). E0 decreases with depolarization to the same extent as does the diliganded gating equilibrium constant, e-fold with ~60 mV. We estimate that at -100 mV the intrinsic energy of the unliganded gating isomerization is +8.4 kcal/mol (35 kJ/mol), and that in the absence of a membrane potential, the intrinsic chemical energy of this global conformational change is +9.4 kcal/mol (39 kJ/mol). Na+ and K+ in the extracellular solution have no measureable effect on E0, which suggests that unliganded gating occurs with only water occupying the transmitter binding sites. The results are discussed with regard to the energy changes in receptor activation and the competitive antagonism of ions in agonist binding. 相似文献
60.