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DNA Elements (dna + element)
Selected AbstractsA human-specific TNF-responsive promoter for Goodpasture antigen-binding proteinFEBS JOURNAL, Issue 20 2005Froilán Granero The Goodpasture antigen-binding protein, GPBP, is a serine/threonine kinase whose relative expression increases in autoimmune processes. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine implicated in autoimmune pathogenesis. Here we show that COL4A3BP, the gene encoding GPBP, maps head-to-head with POLK, the gene encoding for DNA polymerase kappa (pol ,), and shares with it a 140-bp promoter containing a Sp1 site, a TATA-like element, and a nuclear factor kappa B (NF,B)-like site. These three elements cooperate in the assembly of a bidirectional transcription complex containing abundant Sp1 and little NF,B that is more efficient in the POLK direction. Tumour necrosis factor cell induction is associated with Sp1 release, NF,B recruitment and assembly of a complex comparatively more efficient in the COL4A3BP direction. This is accomplished by competitive binding of Sp1 and NF,B to a DNA element encompassing a NF,B-like site that is pivotal for the 140-bp promoter to function. Consistently, a murine homologous DNA region, which contains the Sp1 site and the TATA-like element but is devoid of the NF,B-like site, does not show transcriptional activity in transient gene expression assays. Our findings identify a human-specific TNF-responsive transcriptional unit that locates GPBP in the signalling cascade of TNF and substantiates previous observations, which independently related TNF and GPBP with human autoimmunity. [source] An interferon-sensitive response element is involved in constitutive caspase-8 gene expression in neuroblastoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Alessandro De Ambrosis Abstract We previously identified a 1.2 Kb DNA element (P-1161/+16), 5, to caspase-8 exon-1, that acts as promoter in caspase-8-positive, but not in caspase-8-negative neuroblastoma (NB) cells. The P-1161/+16 DNA element regulates both constitutive and interferon IFN-,-inducible caspase-8 expression. Two GAS (IFN-activated sequence, STAT-1 binding site) and two ISRE (interferon sensitive response element, IRF binding site) were present in P-1161/+16. Deletion studies indicated that elements essential for promoter activity in NB cells were present in a 167 bp region 5, flanking exon-1 (P-151/+16), which contains an ISRE at position ,32. The transcription initiation site was mapped by 5, rapid amplification of cDNA end (RACE) at position ,20 from caspase-8 cDNA reference sequence. Disruption of the ISRE-32 indicated that it is required for both constitutive and IFN-,-inducible caspase-8 expression. IRF-1 and IRF-2 transcription factors bind to the (,151/+16) DNA fragment in vitro. Chromatin immunoprecipitation (ChIP) assays showed that IRF-1 and IRF-2 bind to the DNA region at the 5, of caspase-8 gene in NB cells, which show constitutive expression but not in caspase-8 negative cells. In these last cells, up-regulation of caspase-8 by IFN-, was associated to induction of IRF-1 and IRF-2 binding to caspase-8 promoter and increased histone acetylation. Moreover, RNA interference experiments also supported the involvement of IRF-1 and IRF-2 in constitutive caspase-8 expression in NB cells. © 2006 Wiley-Liss, Inc. [source] Amino-terminus domain of the androgen receptor as a molecular target to prevent the hormonal progression of prostate cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Gang Wang Abstract Prostate cancer has a propensity to metastasize to the bone. Currently the only effective systemic treatment for these patients is androgen ablation therapy. However, the tumor will invariably progress to an androgen-independent stage and the patient will succumb to his disease within approximately 2 years. The earliest indication of hormonal progression is the rising titer of serum prostate specific antigen. Current evidence implicates the androgen receptor (AR) as a key factor in maintaining the growth of prostate cancer cells in an androgen-depleted state. Under normal conditions, binding of ligand activates the receptor, allowing it to effectively bind to its respective DNA element. However, AR is also transformed in the absence of androgen (ligand-independent activation) in prostate cells via multiple protein kinase pathways and the interleukin-6 (IL-6) pathway that converge upon the N-terminal domain of the AR. This domain is the main region for phosphorylation and is also critical for normal coregulator recruitment. Here we discuss evidence supporting the role of the AR, IL-6 and other protein kinase pathways in the hormonal progression of prostate cancer to androgen independence and the mechanisms involved in activation of the AR by these pathways. Receptor-targeted therapy, especially potential drugs targeting the N-terminal domain, may effectively prevent or delay the hormonal progression of AR-dependent prostate cancer. J. Cell. Biochem. 98: 36,53, 2006. © 2006 Wiley-Liss, Inc. [source] Transcriptional activation of human mu-opioid receptor gene by insulin-like growth factor-I in neuronal cells is modulated by the transcription factor RESTJOURNAL OF NEUROCHEMISTRY, Issue 6 2008Andrea Bedini Abstract The human mu-opioid receptor gene (OPRM1) promoter contains a DNA sequence binding the repressor element 1 silencing transcription factor (REST) that is implicated in transcriptional repression. We investigated whether insulin-like growth factor I (IGF-I), which affects various aspects of neuronal induction and maturation, regulates OPRM1 transcription in neuronal cells in the context of the potential influence of REST. A series of OPRM1-luciferase promoter/reporter constructs were transfected into two neuronal cell models, neuroblastoma-derived SH-SY5Y cells and PC12 cells. In the former, endogenous levels of human mu-opioid receptor (hMOPr) mRNA were evaluated by real-time PCR. IGF-I up-regulated OPRM1 transcription in: PC12 cells lacking REST, in SH-SY5Y cells transfected with constructs deficient in the REST DNA binding element, or when REST was down-regulated in retinoic acid-differentiated cells. IGF-I activates the signal transducer and activator of transcription-3 signaling pathway and this transcription factor, binding to the signal transducer and activator of transcription-1/3 DNA element located in the promoter, increases OPRM1 transcription. We propose that a reduction in REST is a critical switch enabling IGF-I to up-regulate hMOPr. These findings help clarify how hMOPr expression is regulated in neuronal cells. [source] The Freud-1/CC2D1A family: Transcriptional regulators implicated in mental retardationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2007Anastasia Rogaeva Abstract The CC2D1A gene family consists of two homologous genes, Freud-1/CC2D1A and Freud-2/CC2D1B, that share conserved domains, including several DM14 domains that are specific to this protein family, a C-terminal helix-loop-helix domain, and a C2 calcium-dependent phospholipid binding domain. Although the function of Freud-2 is unknown, Freud-1 has been shown to function as a transcriptional repressor of the serotonin-1A receptor gene that binds to a novel DNA element (FRE, 5,-repressor element). The DNA binding and repressor activities of Freud-1 are inhibited by calcium-calmodulin-dependent protein kinase. Recently, a deletion in the CC2D1A gene has been linked to nonsyndromic mental retardation. This deletion results in the truncation of the helix-loop-helix DNA binding and the C2 domains, crucial for Freud-1 repressor activity, and hence is predicted to generate an inactive or weakly dominant negative protein. The possible mechanisms by which inactivation of Freud-1 could lead to abnormal cortical development and cognitive impairment and the potential roles of Freud-1 gene targets are discussed. © 2007 Wiley-Liss, Inc. [source] Functional regions of the N-terminal domain of the antiterminator RfaHMOLECULAR MICROBIOLOGY, Issue 2 2010Georgiy A. Belogurov Summary RfaH is a bacterial elongation factor that increases expression of distal genes in several long, horizontally acquired operons. RfaH is recruited to the transcription complex during RNA chain elongation through specific interactions with a DNA element called ops. Following recruitment, RfaH remains bound to RNA polymerase (RNAP) and acts as an antiterminator by reducing RNAP pausing and termination at some factor-independent and Rho-dependent signals. RfaH consists of two domains connected by a flexible linker. The N-terminal RfaH domain (RfaHN) recognizes the ops element, binds to the RNAP and reduces pausing and termination in vitro. Functional analysis of single substitutions in this domain reported here suggests that three separate RfaHN regions mediate these functions. We propose that a polar patch on one side of RfaHN interacts with the non-template DNA strand during recruitment, whereas a hydrophobic surface on the opposite side of RfaHN remains bound to the ,, subunit clamp helices domain throughout transcription of the entire operon. The third region is apparently dispensable for RfaH binding to the transcription complex but is required for the antitermination modification of RNAP. [source] A unique, bifunctional site-specific DNA recombinase from Mycoplasma pulmonisMOLECULAR MICROBIOLOGY, Issue 4 2002Ramakrishnan Sitaraman Summary Site-specific DNA invertible elements often control the production of bacterial surface proteins that are subject to phase variation (ON/OFF switching). Inversion of the DNA element occurs as a result of the reciprocal exchange of DNA catalysed by a specialized enzyme (recombinase) that acts at specific sites. By continually switching the orientation of the invertible element in the chromosome, and consequently the production of the variable protein(s), the cell population remains continually responsive to environmental change such as immunological challenge. In addition to phase-variable surface proteins, Mycoplasma pulmonis has a family of phase-variable restriction-modification enzymes. We report here that a single recombinase in M. pulmonis, HvsR, catalyses independent DNA inversions at non-homologous loci, causing variations in surface lipoproteins and in the DNA recognition sequence specificity of restriction enzymes. Thus, HvsR is a site-specific DNA recombinase with dual substrate specificity. [source] Crystal optimization and preliminary diffraction data analysis of the Smad1 MH1 domain bound to a palindromic SBE DNA elementACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 11 2009Nithya Baburajendran The bone morphogenetic protein (BMP) signalling pathway regulates diverse processes such as cell differentiation, anterior/posterior axis specification, cell growth and the formation of extra-embryonic tissues. The transcription factor Smad1 relays the BMP signal from the cytoplasm to the nucleus, where it binds short DNA-sequence motifs and regulates gene expression. However, how Smad1 selectively targets particular genomic regions is poorly understood. In order to understand the physical basis of the specific interaction of Smad1 with DNA and to contrast it with the highly homologous but functionally distinct Smad3 protein, the DNA-binding Mad-homology 1 (MH1) domain of Smad1 was cocrystallized with a 17-mer palindromic Smad-binding element (SBE). The extensive optimizations of the length, binding-site spacing and terminal sequences of the DNA element in combination with the other crystallization parameters necessary for obtaining diffraction-quality crystals are described here. A 2.7,Å resolution native data set was collected at the National Synchrotron Radiation Research Centre, Taiwan, from crystals grown in a solution containing 0.2,M ammonium tartrate dibasic, 20% PEG 3350, 3% 2-propanol and 10% glycerol. The data set was indexed and merged in space group P222, with unit-cell parameters a = 73.94, b = 77.49, c = 83.78,Å, , = , = , = 90°. The solvent content in the unit cell is consistent with the presence of two Smad1 MH1 molecules bound to the duplex DNA in the asymmetric unit. [source] Megaplasmids in Gram-negative, moderately halophilic bacteriaFEMS MICROBIOLOGY LETTERS, Issue 1 2003Montserrat Argandoña Abstract We have discovered that many Halomonas species harbour large extrachromosomal DNA elements. Using currently available protocols it is technically very difficult to identify large plasmids in bacteria, and even more so when they are coated in mucous polysaccharide. We used culture conditions suitable for both halophilic and halophilic exopolysaccharide-producing bacteria and applied a modified gel electrophoresis method to locate and visualise the megaplasmids. Almost all the species of Halomonas studied harbour two plasmids of about 70 kb and 600 kb and some species carry other smaller extrachromosomal DNA elements. The common presence of these megaplasmids may well be related to the survival strategies of the bacteria in their special surroundings. [source] DNA methylation of Sleeping Beauty with transposition into the mouse genomeGENES TO CELLS, Issue 8 2005Chang Won Park The Sleeping Beauty transposon is a recently developed non-viral vector that can mediate insertion of transgenes into the mammalian genome. Foreign DNA elements that are introduced tend to invoke a host-defense mechanism resulting in epigenetic changes, such as DNA methylation, which may induce transcriptional inactivation of mammalian genes. To assess potential epigenetic modifications associated with Sleeping Beauty transposition, we investigated the DNA methylation pattern of transgenes inserted into the mouse genome as well as genomic regions flanking the insertion sites with bisulfite-mediated genomic sequencing. Transgenic mouse lines were created with two different Sleeping Beauty transposons carrying either the Agouti or eGFP transgene. Our results showed that DNA methylation in the keratin-14 promoter and Agouti transgene were negligible. In addition, two different genomic loci flanking the Agouti insertion site exhibited patterns of DNA methylation similar to wild-type mice. In contrast, high levels of DNA methylation were observed in the eGFP transgene and its ROSA26 promoter. These results indicate that transposition via Sleeping Beauty into the mouse genome may result in a significant level of de novo DNA methylation. This may depend on a number of different factors including the cargo DNA sequence, chromosomal context of the insertion site, and/or host genetic background. [source] Partition of distinct chromosomal regions: negotiable border and fixed borderGENES TO CELLS, Issue 6 2004Akatsuki Kimura Chromosomes are partitioned into distinct functional regions. For example, heterochromatin regions consist of condensed chromatin and contain few transcriptionally active genes, whereas euchromatin regions are less condensed and majority of active genes reside in the euchromatin regions. Because distinct regions reside in each chromosome, borders are accordingly established between these regions. A prevailing view of the borders is that they are ,walls' that actively inhibit communication between distinct regions on chromosomes. Although little is known about the molecular bases of these walls, specific DNA elements are considered to recruit these walls to define the positions of the borders. We call the borders established with this mechanism as ,fixed borders'. Past studies have identified various insulators (boundary DNA elements) that have been suggested to recruit fixed borders to them. Another mechanism, which we introduce and focus on in this review, does not require walls recruited by specific DNA elements at the chromosomal borders. Instead, the borders are defined by a balance of opposing enzymatic activities located at the opposite sides of the resultant borders. We name these borders ,negotiable borders'. Here we review some of the recent progress in the field that offer valuable insight into mechanisms of establishing structural and functional borders on chromosomes. [source] Evolution and spread of antibiotic resistanceJOURNAL OF INTERNAL MEDICINE, Issue 2 2002B. Henriques Normark Abstract., Antibiotic resistance is a clinical and socioeconomical problem that is here to stay. Resistance can be natural or acquired. Some bacterial species, such as Pseudomonas aeruginosa, show a high intrinsic resistance to a number of antibiotics whereas others are normally highly antibiotic susceptible such as group A streptococci. Acquired resistance evolve via genetic alterations in the microbes own genome or by horizontal transfer of resistance genes located on various types of mobile DNA elements. Mutation frequencies to resistance can vary dramatically depending on the mechanism of resistance and whether or not the organism exhibits a mutator phenotype. Resistance usually has a biological cost for the microorganism, but compensatory mutations accumulate rapidly that abolish this fitness cost, explaining why many types of resistances may never disappear in a bacterial population. Resistance frequently occurs stepwise making it important to identify organisms with low level resistance that otherwise may constitute the genetic platform for development of higher resistance levels. Self-replicating plasmids, prophages, transposons, integrons and resistance islands all represent DNA elements that frequently carry resistance genes into sensitive organisms. These elements add DNA to the microbe and utilize site-specific recombinases/integrases for their integration into the genome. However, resistance may also be created by homologous recombination events creating mosaic genes where each piece of the gene may come from a different microbe. The selection with antibiotics have informed us much about the various genetic mechanisms that are responsible for microbial evolution. [source] The identification of circular extrachromosomal DNA in the nuclear genome of Trypanosoma bruceiMOLECULAR MICROBIOLOGY, Issue 2 2003N. S. Alsford Summary Nuclear extrachromosomal DNA elements have been identified in several kinetoplastids such as Leishmania and Trypanosoma cruzi, but never in Trypanosoma brucei. They can occur naturally or arise spontaneously as the result of sublethal drug exposure of parasites. In most cases, they are represented as circular elements and are mitotically unstable. In this study we describe the presence of circular DNA in the nucleus of Trypanosoma brucei. This novel type of DNA was termed NR-element (NlaIII repeat element). In contrast to drug-induced episomes in other kinetoplastids, the T. brucei extrachromosomal NR-element is not generated by drug selection. Furthermore, the element is stable during mitosis over many generations. Restriction analysis of tagged NR-element DNA, unusual migration patterns during pulsed field gel electrophoresis (PFGE) and CsCl/ethidium bromide equilibrium centrifugation demonstrates that the NR-element represents circular DNA. Whereas it has been found in all field isolates of the parasites we analysed, it is not detectable in some laboratory strains notably the genome reference strain 927. The DNA sequence of this element is related to a 29 bp repeat present in the subtelomeric region of VSG-bearing chromosomes of T. brucei. It has been suggested that this subtelomeric region is part of a transition zone on chromosomes separating the relatively stable telomeric repeats from the recombinationaly active region downstream of VSG genes. Therefore, we discuss a functional connection between the occurrence of this circular DNA and subtelomeric recombination events in T. brucei. [source] Mobile DNA elements in primate and human evolutionAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue S45 2007Jinchuan Xing Abstract Roughly 50% of the primate genome consists of mobile, repetitive DNA sequences such as Alu and LINE1 elements. The causes and evolutionary consequences of mobile element insertion, which have received considerable attention during the past decade, are reviewed in this article. Because of their unique mutational mechanisms, these elements are highly useful for answering phylogenetic questions. We demonstrate how they have been used to help resolve a number of questions in primate phylogeny, including the human,chimpanzee,gorilla trichotomy and New World primate phylogeny. Alu and LINE1 element insertion polymorphisms have also been analyzed in human populations to test hypotheses about human evolution and population affinities and to address forensic issues. Finally, these elements have had impacts on the genome itself. We review how they have influenced fundamental ongoing processes like nonhomologous recombination, genomic deletion, and X chromosome inactivation. Yrbk Phys Anthropol 50:2,19, 2007. © 2007 Wiley-Liss, Inc. [source] The soybean Dof-type transcription factor genes, GmDof4 and GmDof11, enhance lipid content in the seeds of transgenic Arabidopsis plantsTHE PLANT JOURNAL, Issue 4 2007Hui-Wen Wang Summary Soybean is one of the most important leguminous seed crops among the oil crops. Although the pathways for lipid biosynthesis have been identified, the factors that regulate the biosynthetic pathways at the transcriptional level are largely unknown. Here, we report our findings on the involvement of soybean Dof-type transcription factor genes in the regulation of the lipid content in soybean seeds. We identified 28 Dof-type transcription factor genes in soybean plants, and these genes displayed diverse patterns of expression in various organs. Seven flower/pod-specific genes and one constitutively expressed gene were further investigated. The proteins encoded by these seven genes were localized in the nucleus, and exhibited different abilities for transcriptional activation and DNA binding. Two genes, GmDof4 and GmDof11, were found to increase the content of total fatty acids and lipids in GmDof4 and GmDof11 transgenic Arabidopsis seeds. We also found that the 1000-seed weight was increased in the GmDof4 and GmDof11 transgenic plants. Using microarray and DNA binding analysis, we found that the two Dof-like proteins, GmDof4 and GmDof11, activated the acetyl CoA carboxylase gene and long-chain-acyl CoA synthetase gene, respectively, by direct binding to the cis -DNA elements in their promoter regions. In addition, both proteins downregulated the storage protein gene, CRA1, through direct binding. These results suggest that the two GmDof genes may augment the lipid content of soybean seeds by upregulating genes that are associated with the biosynthesis of fatty acids. [source] Salinity stress adaptation competence in the extremophile Thellungiella halophila in comparison with its relative Arabidopsis thalianaTHE PLANT JOURNAL, Issue 5 2005Qingqiu Gong Summary In stark contrast to Arabidopsis, a related species, Thellungiella halophila (Thellungiella salsuginea; salt cress), displays extreme tolerance to high salinity, low humidity and freezing. High nucleotide sequence identity permits the use of tools developed for Arabidopsis for Thellungiella transcript profiling, for which a microarray platform with >25 000 DNA elements (70-mer oligonucleotides) was used. Microarray transcript profiling and intensity analysis, quantitative RT-PCR, and metabolite profiles define genes and pathways that showed shared and divergent responses to salinity stress in the two species. Shared responses are exemplified by 40% of the regulated genes functioning in confining ribosomal functions, photosynthesis and cell growth, as well as activating osmolyte production, transport activities and abscisic acid-dependent pathways. An additional 60% of regulated genes distinguished Thellungiella from Arabidopsis. Analysis of the differences showed that Arabidopsis exhibited a global defense strategy that required bulk protein synthesis, while Thellungiella induced genes functioning in protein folding, post-translational modification and protein redistribution. At 150 mm NaCl, Thellungiella maintained unimpeded growth. Transcript intensity analyses and metabolite profiles supported the microarray results, pointing towards a stress-anticipatory preparedness in Thellungiella. [source] Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression,THE PROSTATE, Issue 9 2010JianFeng Zhang Abstract BACKGROUND The androgen-regulated probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis -acting DNA elements. METHODS Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a "pioneer factor" that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (,244/,96,bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression. Prostate 70: 934,951, 2010. © 2010 Wiley-Liss, Inc. [source] The interplay between transcription factors and microRNAs in genome-scale regulatory networksBIOESSAYS, Issue 4 2009Natalia J. Martinez Abstract Metazoan genomes contain thousands of protein-coding and non-coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans -regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis -regulatory DNA elements that are often located in or near their target genes, while miRNAs hybridize to cis -regulatory RNA elements mostly located in the 3, untranslated region of their target mRNAs. Here, we describe how these trans -regulators interact with each other in the context of gene regulatory networks to coordinate gene expression at the genome-scale level, and discuss future challenges of integrating these networks with other types of functional networks. [source] Bean Yellow Dwarf Virus replicons for high-level transgene expression in transgenic plants and cell culturesBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2006Xiuren Zhang Abstract A novel stable transgenic plant expression system was developed using elements of the replication machinery of Bean Yellow Dwarf Virus (BeYDV). The system contains two transgenes: 1) The BeYDV replicon vector with an expression cassette flanked by cis -acting DNA elements of BeYDV, and 2) The viral replication initiator protein (Rep) controlled by an alcohol-inducible promoter. When Rep expression was triggered by treatment with ethanol, it induced release of the BeYDV replicon from stably integrated T-DNA and episomal replication to high copy number. Replicon amplification resulted in substantially increased transgene mRNA levels (up to 80-fold) and translation products (up to 10-fold) after induction of Rep expression by ethanol treatment in tobacco NT1 cells and leaves of whole potato plants. Thus, the BeYDV stable transformant replicon system is a powerful tool for plant-based production of recombinant proteins. © 2005 Wiley Periodicals, Inc. [source] "Natural restoration" can generate biological complexityCOMPLEXITY, Issue 2 2005Emile ZuckerkandlArticle first published online: 16 DEC 200 Abstract Factor complexes engaged in transcriptional regulation of gene expression and their cognate DNA elements recurrently suffer mutational damage that can result in deadaptations in the mutual fit of interacting macromolecules. Such mutations can spread in populations by drift if their functional consequences are not severe. Mutational restorations of the damaged complexes may ensue and can take many forms. One of these forms would represent spontaneous increases in gene interaction complexity and correlated aspects of organismic complexity. In this particular mode of restoration, restabilization of a factor/factor/DNA complex occurs through the binding of an additional factor. Factors added under such circumstances to regulatory kits of individual genes are thought to be at the origin of a slow but persistent "complexity drive." This drive seems to be resisted in many forms whose developmental outcome has reached a finish line difficult to pass, but imposes itself along other lines of phylogenetic descent. In the process of restoration by an additional factor, the chances are significant that the original regulatory control of a target gene is not recovered exactly and that the restored gene expression has novel spatial, temporal, or quantitative characteristics. These new characteristics, which represent a functional transfer of the gene to a new domain of activity, may be selectable, even when the physicochemical properties of the gene product have remained largely unchanged. As a consequence of such activity transfers under quasi-constancy of the molecular properties of the protein encoded by the regulation's target gene, the activity domain originally covered by that target gene may be left at least in part functionally vacant. At that point, an unmodified duplicate of the target gene and of its original regulatory dependencies probably becomes in turn selectable. A causal link is therefore predicted between the regulatory specialization and selection of one of two duplicates and the regulatory maintenance and selection of the other. A conserved increase in gene number would result indirectly from the regulatory shift in paralogs, and the organism's complexity would be increased in this sense also, complexity as number of genes in addition to complexity as number of regulatory factors per gene. It is thus proposed that increased biological complexity, innovation in the gene regulatory network, and the development of a novel evolutionary potential can be the result, counterintuitively, of conservative forces that intervene when mutations play a survivable form of havoc with the system of gene regulation. Increasing complexity, then, could be seen as one of the side effects of "natural restoration." This phrase designates the mutational re-establishment in the gene whose regulation has been damaged of a functionally effective activity pattern, albeit, perhaps, with changes in its mode of expression in regard to location, time, and rate. The higher complexity, innovation in the gene regulatory network, of higher organisms,their very character of higher organisms,would to a significant extent be a side effect of episodes of natural selection aimed at functional restoration, not at complexity itself. Regulatory impairment, the point of departure of the process outlined, represents a controller gene disease. It thus may well be the case that molecular diseases, the effects on the individual of inheritable structural decay, are among the conditions of the evolution of higher organisms. © 2005 Wiley Periodicals, Inc. Complexity 11: 14,27, 2005 [source] | ||||||||||||||||||||||||||||