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The Evolution of Two-Component Systems in Bacteria RevealsDifferent Strategies for Niche Adaptation

Description: Two-component systems including histidine protein kinasesrepresent the primary signal transduction paradigm in prokaryoticorganisms. To understand how these systems adapt to allow organisms todetect niche-specific signals, we analyzed the phylogenetic distributionof nearly 5000 histidine protein kinases from 207 sequenced prokaryoticgenomes. We found that many genomes carry a large repertoire of recentlyevolved signaling genes, which may reflect selective pressure to adapt tonew environmental conditions. Both lineage-specific gene family expansionand horizontal gene transfer play major roles in the introduction of newhistidine kinases into genomes; however, there are differences in howthese two evolutionary forces act. Genes imported via horizontal transferare more likely to retain their original functionality as inferred from asimilar complement of signaling domains, while gene family expansionaccompanied by domain shuffling appears to be a major source of novelgenetic diversity. Family expansion is the dominantsource of newhistidine kinase genes in the genomes most enriched in signalingproteins, and detailed analysis reveals that divergence in domainstructure and changes in expression patterns are hallmarks of recentexpansions. Finally, while these two modes of gene acquisition arewidespread across bacterial taxa, there are clear species-specificpreferences for which mode is used.
Date: September 13, 2006
Creator: Alm, Eric; Huang, Katherine & Arkin, Adam
Partner: UNT Libraries Government Documents Department

Erythroblastic Islands: Specialized Mircoenvironmental Niches forErythropoiesis

Description: This review focuses on current understanding of molecular mechanisms operating within erythroblastic islands including cell-cell adhesion, regulatory feedback, and central macrophage function. RECENT FINDINGS: Erythroblasts express a variety of adhesion molecules and recently two interactions have been identified that appear to be critical for island integrity. Erythroblast macrophage protein, expressed on erythroblasts and macrophages, mediates cell-cell attachments via homophilic binding. Erythroblast intercellular adhesion molecule-4 links erythroblasts to macrophages through interaction with macrophage alphav integrin. In intercellular adhesion molecule-4 knockout mice, erythroblastic islands are markedly reduced, whereas the erythroblast macrophage protein null phenotype is severely anemic and embryonic lethal. Retinoblastoma tumor suppressor (Rb) protein stimulates macrophage differentiation by counteracting inhibition of Id2 on PU.1, a transcription factor that is a crucial regulator of macrophage differentiation. Rb-deficient macrophages do not bind Rb null erythroblasts and the Rb null phenotype is anemic and embryonic lethal. Lastly, extruded nuclei rapidly expose phosphatidylserine on their surface, providing a recognition signal similar to apoptotic cells. SUMMARY: Although understanding of molecular mechanisms operating within islands is at an early stage, tantalizing evidence suggests that erythroblastic islands are specialized niches where intercellular interactions in concert with cytokines play critical roles in regulating erythropoiesis.
Date: January 6, 2006
Creator: Chasis, Joel Anne
Partner: UNT Libraries Government Documents Department

New High Performance Magnet Structures for Bead Based MolecularSeparation

Description: New High Performance Magnet Structures for Bead Based Molecular Separation David Humphries Lawrence Berkeley National Laboratory, D.O.E. Joint Genome Institute Abstract High performance Hybrid magnetic separation technology is under continuing development at the D.O.E. Joint Genome Institute and Lawrence Berkeley National Laboratory for general laboratory and high throughput automated applications. This technology has broad applicability for molecular separation in genomics, proteomics and other areas. It s applicability ranges from large and small scale microtiter plate and flow separation processes to single molecule DNA manipulation. It is currently an enabling purification technology for very high throughput production sequencing at the D.O.E. Joint Genome Institute. This technology incorporates hybrid magnetic structures that combine linear permanent magnet material and ferromagnetic material to produce significantly higher fields and gradients than those of currently available commercial devices. These structures incorporate ferromagnetic poles that can be easily shaped to produce complex field distributions for specialized applications. The higher maximum fields and strong gradients of the hybrid structures result in greater holding forces on magnetized targets that are being processed as well as faster extraction. Current development versions of these magnet plates have exhibited fields in excess of 1.0 tesla and gradients approaching 1000.0 tesla/meter. Second generation Hybrid magnet plates have now been developed for both 384 and 96-well applications. This technology is currently being made available to industry through the Tech Transfer Department at Lawrence Berkeley National Laboratory. This work was performed under the auspices of the US Department of Energy's Office of Science, Biological and Environmental Research Program and the by the University of California, Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48, Lawrence Berkeley National Laboratory under contract No. DE-AC03-6SF00098 and Los Alamos National Laboratory under contract No. W-7405-ENG-36.
Date: June 1, 2005
Creator: Humphries, David
Partner: UNT Libraries Government Documents Department

The histone H3K9 methylation and RNAi pathways regulate normalnucleolar and repeated DNA organization by inhibiting formation ofextrachromosomal DNAs

Description: In order to identify regulators of nuclear organization, Drosophila mutants in the Su(var)3-9 histone H3K9 methyltransferase, RNAi pathway components, and other regulators of heterochromatin-mediated gene silencing were examined for altered nucleoli and positioning of repeated DNAs. Animals lacking components of the H3K9 methylation and RNAi pathways contained disorganized nucleoli, ribosomal DNA (rDNA) and satellite DNAs. The levels of H3K9 dimethylation (H3K9me2) in chromatin associated with repeated DNAs decreased dramatically in Su(var)3-9 and dcr-2 (dicer-2) mutant tissues compared to wild type. We also observed a substantial increase in extrachromosomal repeated DNAs in mutant tissues. The disorganized nucleolus phenotype depends on the presence of Ligase 4 (Lig4), and ecc DNA formation is not induced by removal of cohesin. We conclude that H3K9 methylation of rDNA and satellites, maintained by Su(var)3-9, HP1, and the RNAi pathway, is necessary for the structural stability of repeated DNAs, which is mediated through suppression of non-homologous end joining (NHEJ). These results suggest a mechanism for how local chromatin structure can regulate genome stability, and the organization of chromosomal elements and nuclear organelles.
Date: June 15, 2006
Creator: Peng, Jamy C. & Karpen, Gary H.
Partner: UNT Libraries Government Documents Department

OpWise: Operons aid the identification of differentially expressedgenes in bacterial microarray experiments

Description: Differentially expressed genes are typically identified by analyzing the variation between replicate measurements. These procedures implicitly assume that there are no systematic errors in the data even though several sources of systematic error are known. Results-OpWise estimates the amount of systematic error in bacterial microarray data by assuming that genes in the same operon have matching expression patterns. OpWise then performs a Bayesian analysis of a linear model to estimate significance. In simulations, OpWise corrects for systematic error and is robust to deviations from its assumptions. In several bacterial data sets, significant amounts of systematic error are present, and replicate-based approaches overstate the confidence of the changers dramatically, while OpWise does not. Finally, OpWise can identify additional changers by assigning genes higher confidence if they are consistent with other genes in the same operon. Although microarray data can contain large amounts of systematic error, operons provide an external standard and allow for reasonable estimates of significance. OpWise is available at http://microbesonline.org/OpWise.
Date: November 23, 2005
Creator: Price, Morgan N.; Arkin, Adam P. & Alm, Eric J.
Partner: UNT Libraries Government Documents Department

Comparative genomic analysis as a tool for biologicaldiscovery

Description: Biology is a discipline rooted in comparisons. Comparative physiology has assembled a detailed catalogue of the biological similarities and differences between species, revealing insights into how life has adapted to fill a wide-range of environmental niches. For example, the oxygen and carbon dioxide carrying capacity of vertebrate has evolved to provide strong advantages for species respiring at sea level, at high elevation or within water. Comparative- anatomy, -biochemistry, -pharmacology, -immunology and -cell biology have provided the fundamental paradigms from which each discipline has grown.
Date: March 30, 2003
Creator: Nobrega, Marcelo A. & Pennacchio, Len A.
Partner: UNT Libraries Government Documents Department

DNA repair: Dynamic defenders against cancer and aging

Description: You probably weren't thinking about your body's cellular DNA repair systems the last time you sat on the beach in the bright sunshine. Fortunately, however, while you were subjecting your DNA to the harmful effects of ultraviolet light, your cells were busy repairing the damage. The idea that our genetic material could be damaged by the sun was not appreciated in the early days of molecular biology. When Watson and Crick discovered the structure of DNA in 1953 [1], it was assumed that DNA is fundamentally stable since it carries the blueprint of life. However, over 50 years of research have revealed that our DNA is under constant assault by sunlight, oxygen, radiation, various chemicals, and even our own cellular processes. Cleverly, evolution has provided our cells with a diverse set of tools to repair the damage that Mother Nature causes. DNA repair processes restore the normal nucleotide sequence and DNA structure of the genome after damage [2]. These responses are highly varied and exquisitely regulated. DNA repair mechanisms are traditionally characterized by the type of damage repaired. A large variety of chemical modifications can alter normal DNA bases and either lead to mutations or block transcription if not repaired, and three distinct pathways exist to remove base damage. Base excision repair (BER) corrects DNA base alterations that do not distort the overall structure of the DNA helix such as bases damaged by oxidation resulting from normal cellular metabolism. While BER removes single damaged bases, nucleotide excision repair (NER) removes short segments of nucleotides (called oligonucleotides) containing damaged bases. NER responds to any alteration that distorts the DNA helix and is the mechanism responsible for repairing bulky base damage caused by carcinogenic chemicals such as benzo [a]pyrene (found in cigarette smoke and automobile exhaust) as well as covalent linkages between ...
Date: April 1, 2006
Creator: Fuss, Jill O. & Cooper, Priscilla K.
Partner: UNT Libraries Government Documents Department

An adaptive radiation model for the origin of new genefunctions

Description: The evolution of new gene functions is one of the keys to evolutionary innovation. Most novel functions result from gene duplication followed by divergence. However, the models hitherto proposed to account for this process are not fully satisfactory. The classic model of neofunctionalization holds that the two paralogous gene copies resulting from a duplication are functionally redundant, such that one of them can evolve under no functional constraints and occasionally acquire a new function. This model lacks a convincing mechanism for the new gene copies to increase in frequency in the population and survive the mutational load expected to accumulate under neutrality, before the acquisition of the rare beneficial mutations that would confer new functionality. The subfunctionalization model has been proposed as an alternative way to generate genes with altered functions. This model also assumes that new paralogous gene copies are functionally redundant and therefore neutral, but it predicts that relaxed selection will affect both gene copies such that some of the capabilities of the parent gene will disappear in one of the copies and be retained in the other. Thus, the functions originally present in a single gene will be partitioned between the two descendant copies. However, although this model can explain increases in gene number, it does not really address the main evolutionary question, which is the development of new biochemical capabilities. Recently, a new concept has been introduced into the gene evolution literature which is most likely to help solve this dilemma. The key point is to allow for a period of natural selection for the duplication per se, before new function evolves, rather than considering gene duplication to be neutral as in the previous models. Here, I suggest a new model that draws on the advantage of postulating selection for gene duplication, and proposes that bursts ...
Date: October 18, 2004
Creator: Francino, M. Pilar
Partner: UNT Libraries Government Documents Department

Application of Sequence-based Methods in Human MicrobialEcology

Description: Ecologists studying microbial life in the environment have recognized the enormous complexity of microbial diversity for many years, and the development of a variety of culture-independent methods, many of them coupled with high-throughput DNA sequencing, has allowed this diversity to be explored in ever greater detail. Despite the widespread application of these new techniques to the characterization of uncultivated microbes and microbial communities in the environment, their application to human health and disease has lagged behind. Because DNA based-techniques for defining uncultured microbes allow not only cataloging of microbial diversity, but also insight into microbial functions, investigators are beginning to apply these tools to the microbial communities that abound on and within us, in what has aptly been called the second Human Genome Project. In this review we discuss the sequence-based methods for microbial analysis that are currently available and their application to identify novel human pathogens, improve diagnosis of known infectious diseases, and to advance understanding of our relationship with microbial communities that normally reside in and on the human body.
Date: August 29, 2005
Creator: Weng, Li; Rubin, Edward M. & Bristow, James
Partner: UNT Libraries Government Documents Department

An Experimental Metagenome Data Management and AnalysisSystem

Description: The application of shotgun sequencing to environmental samples has revealed a new universe of microbial community genomes (metagenomes) involving previously uncultured organisms. Metagenome analysis, which is expected to provide a comprehensive picture of the gene functions and metabolic capacity of microbial community, needs to be conducted in the context of a comprehensive data management and analysis system. We present in this paper IMG/M, an experimental metagenome data management and analysis system that is based on the Integrated Microbial Genomes (IMG) system. IMG/M provides tools and viewers for analyzing both metagenomes and isolate genomes individually or in a comparative context.
Date: March 1, 2006
Creator: Markowitz, Victor M.; Korzeniewski, Frank; Palaniappan, Krishna; Szeto, Ernest; Ivanova, Natalia N.; Kyrpides, Nikos C. et al.
Partner: UNT Libraries Government Documents Department

Strategies and tools for whole genome alignments

Description: The availability of the assembled mouse genome makespossible, for the first time, an alignment and comparison of two largevertebrate genomes. We have investigated different strategies ofalignment for the subsequent analysis of conservation of genomes that areeffective for different quality assemblies. These strategies were appliedto the comparison of the working draft of the human genome with the MouseGenome Sequencing Consortium assembly, as well as other intermediatemouse assemblies. Our methods are fast and the resulting alignmentsexhibit a high degree of sensitivity, covering more than 90 percent ofknown coding exons in the human genome. We have obtained such coveragewhile preserving specificity. With a view towards the end user, we havedeveloped a suite of tools and websites for automatically aligning, andsubsequently browsing and working with whole genome comparisons. Wedescribe the use of these tools to identify conserved non-coding regionsbetween the human and mouse genomes, some of which have not beenidentified by other methods.
Date: November 25, 2002
Creator: Couronne, Olivier; Poliakov, Alexander; Bray, Nicolas; Ishkhanov,Tigran; Ryaboy, Dmitriy; Rubin, Edward et al.
Partner: UNT Libraries Government Documents Department

Induced polarization response of microbial induced sulfideprecipitation

Description: A laboratory scale experiment was conducted to examine the use of induced polarization and electrical conductivity to monitor microbial induced sulfide precipitation under anaerobic conditions in sand filled columns. Three columns were fabricated; one for electrical measurements, one for geochemical sampling and a third non-inoculated column was used as a control. A continual upward flow of nutrients and metals in solution was established in each column. Desulfovibrio vulgaris microbes were injected into the middle of the geochemical and electrical columns. Iron and zinc sulfides precipitated along a microbial action front as a result of sulfate reduction due by Desulfovibrio vulgaris. The precipitation front initially developed near the microbial injection location, and subsequently migrated towards the nutrient inlet, as a result of chemotaxis by Desulfovibrio vulgaris. Sampling during and subsequent to the experiment revealed spatiotemporal changes in the biogeochemical measurements associated with microbial sulfate reduction. Conductivity measurements were insensitive to all biogeochemical changes occurred within the column. Changes in the IP response (of up to 14 mrad)were observed to coincide in place and in time with the active microbe respiration/sulfide precipitation front as determined from geochemical sampling. The IP response is correlated with the lactate concentration gradient, an indirect measurement of microbial metabolism, suggesting the potential of IP as a method for monitoring microbial respiration/activity. Post experimental destructive sample analysis and SEM imaging verified the geochemical results and supported our hypothesis that microbe induced sulfide precipitation is directly detectable using electrical methods. Although the processes not fully understood, the IP response appears to be sensitive to this anaerobic microbial precipitation, suggesting a possible novel application for the IP method.
Date: June 4, 2004
Creator: Ntarlagiannis, Dimitrios; Williams, Kenneth Hurst; Slater, Lee & Hubbard, Susan
Partner: UNT Libraries Government Documents Department

Joint inversion of geophysical and hydrological data for improvedsubsurface characterization

Description: Understanding fluid distribution and movement in the subsurface is critical for a variety of subsurface applications, such as remediation of environmental contaminants, sequestration of nuclear waste and CO2, intrusion of saline water into fresh water aquifers, and the production of oil and gas. It is well recognized that characterizing the properties that control fluids in the subsurface with the accuracy and spatial coverage needed to parameterize flow and transport models is challenging using conventional borehole data alone. Integration of conventional borehole data with more spatially extensive geophysical data (obtained from the surface, between boreholes, and from surface to boreholes) shows promise for providing quantitative information about subsurface properties and processes. Typically, estimation of subsurface properties involves a two-step procedure in which geophysical data are first inverted and then integrated with direct measurements and petrophysical relationship information to estimate hydrological parameters. However, errors inherent to geophysical data acquisition and inversion approaches and errors associated with petrophysical relationships can decrease the value of geophysical data in the estimation procedure. In this paper, we illustrate using two examples how joint inversion approaches, or simultaneous inversion of geophysical and hydrological data, offer great potential for overcoming some of these limitations.
Date: April 3, 2006
Creator: Kowalsky, Michael B.; Chen, Jinsong & Hubbard, Susan S.
Partner: UNT Libraries Government Documents Department

The Life-cycle of Operons

Description: Operons are a major feature of all prokaryotic genomes, but how and why operon structures vary is not well understood. To elucidate the life-cycle of operons, we compared gene order between Escherichia coli K12 and its relatives and identified the recently formed and destroyed operons in E. coli. This allowed us to determine how operons form, how they become closely spaced, and how they die. Our findings suggest that operon evolution is driven by selection on gene expression patterns. First, both operon creation and operon destruction lead to large changes in gene expression patterns. For example, the removal of lysA and ruvA from ancestral operons that contained essential genes allowed their expression to respond to lysine levels and DNA damage, respectively. Second, some operons have undergone accelerated evolution, with multiple new genes being added during a brief period. Third, although most operons are closely spaced because of a neutral bias towards deletion and because of selection against large overlaps, highly expressed operons tend to be widely spaced because of regulatory fine-tuning by intervening sequences. Although operon evolution seems to be adaptive, it need not be optimal: new operons often comprise functionally unrelated genes that were already in proximity before the operon formed.
Date: November 18, 2005
Creator: Price, Morgan N.; Arkin, Adam P. & Alm, Eric J.
Partner: UNT Libraries Government Documents Department

Advantages of improved timing accuracy in PET cameras using LSOscintillator

Description: PET scanners based on LSO have the potential forsignificantly better coincidence timing resolution than the 6 ns fwhmtypically achieved with BGO. This study analyzes the performanceenhancements made possible by improved timing as a function of thecoincidence time resolution. If 500 ps fwhm coincidence timing resolutioncan be achieved in a complete PET camera, the following four benefits canbe realized for whole-body FDG imaging: 1) The random event rate can bereduced by using a narrower coincidence timing window, increasing thepeak NECR by~;50 percent. 2) Using time-of-flight in the reconstructionalgorithm will reduce the noise variance by a factor of 5. 3) Emissionand transmission data can be acquired simultaneously, reducing the totalscan time. 4) Axial blurring can be reduced by using time-of-flight todetermine the correct axial plane that each event originated from. Whiletime-of-flight was extensively studied in the 1980's, practical factorslimited its effectiveness at that time and little attention has been paidto timing in PET since then. As these potential improvements aresubstantial and the advent of LSO PET cameras gives us the means toobtain them without other sacrifices, efforts to improve PET timingshould resume after their long dormancy.
Date: December 2, 2002
Creator: Moses, William W.
Partner: UNT Libraries Government Documents Department

Mislocalization of the Drosophila centromere-specific histone CIDpromotes formation of functional ectopic kinetochores

Description: The centromere-specific histone variant CENP-A (CID in Drosophila) is a structural and functional foundation for kinetochore formation and chromosome segregation. Here, we show that overexpressed CID is mislocalized into normally non-centromeric regions in Drosophila tissue culture cells and animals. Analysis of mitoses in living and fixed cells reveals that mitotic delays, anaphase bridges, chromosome fragmentation, and cell and organismal lethality are all direct consequences of CID mislocalization. In addition, proteins that are normally restricted to endogenous kinetochores assemble at a subset of ectopic CID incorporation regions. The presence of microtubule motors and binding proteins, spindle attachments, and aberrant chromosome morphologies demonstrate that these ectopic kinetochores are functional. We conclude that CID mislocalization promotes formation of ectopic centromeres and multicentric chromosomes, which causes chromosome missegregation, aneuploidy, and growth defects. Thus, CENP-A mislocalization is one possible mechanism for genome instability during cancer progression, as well as centromere plasticity during evolution.
Date: January 30, 2006
Creator: Heun, Patrick; Erhardt, Sylvia; Blower, Michael D.; Weiss,Samara; Skora, Andrew D. & Karpen, Gary H.
Partner: UNT Libraries Government Documents Department

Processing of 3'-Phosphoglycolate-Terminated DNA Double-StrandBreaks by Artemis Nuclease

Description: The Artemis nuclease is required for V(D)J recombination and for repair of an as yet undefined subset of radiation-induced DNA double-strand breaks. To assess the possibility that Artemis functions on oxidatively modified double-strand break termini, its activity toward model DNA substrates, bearing either 3{prime}-hydroxyl or 3{prime}-phosphoglycolate moieties, was examined. A 3{prime}-phosphoglycolate had little effect on Artemis-mediated trimming of long 3{prime} overhangs (>9 nucleotides), which were efficiently trimmed to 4-5 nucleotides. However, 3{prime}-phosphoglycolates on overhangs of 4-5 bases promoted selective Artemis-mediated trimming of a single 3{prime}-terminal nucleotide, while at least 2 nucleotides were trimmed from identical hydroxyl-terminated substrates. Artemis also efficiently removed a single nucleotide from a phosphoglycolate-terminated 3-base 3{prime} overhang, while leaving an analogous hydroxyl-terminated overhang largely intact. Such removal was dependent upon Ku, DNA-dependent protein kinase, and ATP. Together, these data suggest that Artemis-mediated cleavage of 3{prime} overhangs requires a minimum of 2 nucleotides, or a nucleotide plus a phosphoglycolate, 3{prime} to the cleavage site. Shorter 3{prime}-phosphoglycolate-terminated overhangs and blunt ends were also processed by Artemis, but much less efficiently. Consistent with the in vitro substrate specificity of Artemis, human cells lacking Artemis exhibited hypersensitivity to X-rays, bleomycin and neocarzinostatin, which all induce 3{prime}-phosphoglycolate-terminated double-strand breaks. Collectively, these results suggest that 3{prime}-phosphoglycolate termini and/or specific classes of DNA ends that arise from such blocked termini are relevant Artemis substrates in vivo.
Date: October 1, 2005
Creator: Povrik, Lawrence F.; Zhou, Tong; Zhou, Ruizhe; Cowan, Morton J. & Yannone, Steven M.
Partner: UNT Libraries Government Documents Department

Factors influencing timing resolution in a commercial LSO PETcamera

Description: The CPS Accel is a commercial PET camera based on a block detector with 64 LSO scintillator crystals (each 6.75 x 6.75 x 25 mm)read out with 4 photomultiplier tubes. The excellent timing resolution of LSO suggests that this camera might be used for time-of-flight (TOF) PET, thereby reducing the statistical noise significantly. Although the Accel achieves 3 ns coincidence resolution (a factor of two better than BGO-based PET cameras), its timing resolution is nearly an order of magnitude worse than that demonstrated with individual LSO crystals. This paper quantifies the effect on the timing of each component in the Accel timing chain to identify which components most limit the camera's timing resolution. The components in the timing chain are: the scintillator crystal, the photomultiplier tube (PMT), the constant fraction discriminator (CFD), and the time to digital converter (TDC). To measure the contribution of each component, we construct a single crystal test system with high-performance versions of these components. This system achieves 221 ps fwhm coincidence timing resolution, which is used as a baseline measurement. One of the high-performance components is replaced by a production component, the coincidence timing resolution is re-measured, and the difference between measurements is the contribution of that (production) component. We find that the contributions of the TDC, CFD, PMT, and scintillator are 2000 ps, 1354 ps, 422 ps, and 326 psfwhm respectively, and that the overall timing resolution scales like the square root of the amount of scintillation light detected by the PMT. Based on these measurements we predict that the limit for the coincidence timing resolution in a practical, commercial, LSO-based PET camera is 528ps fwhm.
Date: October 23, 2004
Creator: Moses, William W. & Ullisch, Marcus
Partner: UNT Libraries Government Documents Department

The single-strand DNA binding activity of human PC4 preventsmutagenesis and killing by oxidative DNA damage

Description: Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as a suppressor of the oxidative mutator phenotype of the Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA binding activity. Yeast mutants lacking their PC4 ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and peroxide induced hypermutability. PC4 expression suppresses the peroxide sensitivity of the yeast sub l{Delta} mutant, suggesting that the human protein has a similar function. A role for yeast and human proteins in DNA repair is suggested by the demonstration that Sub1 acts in a peroxide-resistance pathway involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog XPG. We show XPG recruits PC4 to a bubble-containing DNA substrate with resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the possible requirement for PC4 in either global or transcription-coupled repair of oxidative DNA damage to mediate the release of XPG bound to its substrate.
Date: February 1, 2004
Creator: Wang, Jen-Yeu; Sarker, Altaf Hossain; Cooper, Priscilla K. & Volkert, Michael R.
Partner: UNT Libraries Government Documents Department