bluuebunny/crossref_metadata_2025 huggingface dataset:
Problems and paradigms: Fine tuning of DNA repair in transcribed genes: Mechanisms, prevalence and consequences
Authors: Downes C. Stephen , Ryan Anderson J. , Johnson Robert T.
Published: February 2005

Cells fine‐tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV‐induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair‐defective diseases may involve repair‐transcription coupling: three candidate genes have been suggested.

However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription.

Repair of other damage departs further from the paradigm, even in some UV‐mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV‐induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted.
Genes controlling nucleotide excision repair in eukaryotic cells
Authors: Weeda Geert , Hoeijmakers Jan H. J. , Bootsma Dirk
Published: February 2005

The maintenance of genetic integrity is of vital importance to all living organisms. However, DNA – the carrier of genetic information – is continuously subject to damage induced by numerous agents from the environment and endogenous cellular metabolites. To prevent the deleterious consequences of DNA injury, an intricate network of repair systems has evolved. The biological impact of these repair mechanisms is illustrated by a number of genetic diseases that are characterized by a defect in one of the repair machineries and in general predispose individuals to cancer. This article intends to review our current understanding of the complex nucleotide excision repair pathway, a universal repair system with a broad lesion specificity. Emphasis will be on the recent advances in the genetic analysis of this process in mammalian cells.
Problems and paradigms: Is segmentation generic?
Authors: Newman Stuart A.
Published: February 2005

When two populations of cells within a tissue mass differ from one another in magnitude or type of intercellular adhesions, a boundary can form within the tissue, across which cells will fail to mix. This phenomenon may occur regardless of the identity of the molecules that mediate cell adhesion. If, in addition, a choice between the two adhesive states is regulated by a molecule the concentration of which is periodic in space, or in time, then alternating bands of non‐mixing tissue, or segments, can form. But temporal or spatial periodicities in concentration will tend to arise for any molecule that is positively autoregu‐latory. It is therefore proposed that segmentation is a ‘generic’ property of metazoan organisms, and that metamerism would be expected to have emerged numerous times during evolution. A simple model of segmentation, based solely on differential adhesion and periodic regulation of adhesion, can account for segment properties as disparate as those seen in long and short germ band insects, and for diverse experimental results on boundary regeneration in the chick hind brain and the insect cuticle. It is suggested that the complex, multicom‐ponent segment‐forming systems found in contemporary organisms (e.g., Drosophila) are the products of evolutionary recruitment of molecular cues such as homeobox gene products, that increase the reliability and stability of metameric patterns originally templated by generic self‐organizing properties of tissues.
The specification of sensory neuron identity in Drosophila
Authors: Ghysen Alain , Dambly‐Chaudière Christine
Published: February 2005

Different types of sense organs are present on the larva of Drosophila. Several genes that specify the type of sense organ that will form at a particular position have been recently identified. Here we review the functional and molecular analyses of these genes, and summarize the evidence which supports a role in the choice of which type of organ will be formed. Most or all of these genes are required for the appropriate specification of adult as well as larval sense organs, suggesting that the larval and adult systems share many gene requirements. Interestingly, the specifying genes identified so far in the peripheral nervous system are also expressed in subsets of cells in the central nervous system, where they might have similar roles.
Hypothesis. RuvA, RuvB and RuvC proteins: Cleaning‐up after recombinational repairs in E. coli
Authors: Kuzminov Andrei
Published: February 2005

After the completion of RecA protein‐mediated recombinational repair of daughter‐strand gaps in E. coli, participating chromosomes are held together by Holliday junctions. Until recently, it was not known how the cell disengages the connected chromosomes. Accumulating genetic data suggested that the product of the ruv locus participates in recombinational repair and acts after the formation of Holliday junctions. Molecular characterization of the locus revealed that there are three genes – ruvA, ruvB and ruvC; mutations in any one of the genes confer the same phenotype. Recently, the RuvC protein was found to be a Holliday junction resolvase. At first glance, the resolving activity of RuvC alone would appear to be sufficient for the separation of recombining chromosomes. However, in vitro studies show that the filament of RecA protein is unable to dissociate from the products of the recombination reaction. Thus, in vivo, even if the Holliday junctions are resolved by RuvC, RecA filament must be holding two DNA duplexes together. New findings about enzymatic activities of RuvA and RuvB proteins foster the hope that the machinery for removing the RecA filament from DNA has been found.
Molecular biology of double‐minute chromosomes
Authors: Hahn Peter J.
Published: February 2005

Double‐minute chromosomes play a critical role in tumor cell genetics where they are frequently associated with the overexpression of oncogene products. They have been observed for many years in light microscopic examinations of metaphase chromosomes from tumor cells, but their origin remains unknown and is the subject of considerable speculation. However, molecular details of their structure and organization can now be described in conjunction with the microscopic examinations, to allow an evaluation of the various models that have been developed to explain the genesis of double‐minutes. The evidence now favors simple models that invoke chromosome breakage and circularization of very large acentric chromosome fragments, permitting unequal segregation of the genes on the fragment during cell division. If there is selection for overexpression of one of the genes on the fragment, daughter cells with more fragments will grow faster than daughter cells with fewer fragments, and over time the population of cells will come to contain many double‐minutes per cell.
What's new: Conditional cell ablation in Drosophila
Authors: Sentry J. W. , Yang M. M. , Kaiser K.
Published: February 2005

Targeting of cell ablation agents under the control of tissue‐specific promoters promises to be an important tool for studies of development and function in higher organisms. Temperature‐sensitive cell ablation agents, recently developed for Drosophila, extend control to temporal as well as spatial aspects of toxin expression. Here we discuss achievements to date, together with a novel form of enhancer trap technology with the potential for driving toxin expression in a large range of cell types.
What the papers say: Telomeric DNA binding proteins
Authors: Lin Jing‐Jer
Published: February 2005

The physical ends of eukaryotic chromosomes form a specialized nucleoprotein complex composed of DNA and DNA binding proteins. This nucleoprotein complex, termed the telomere, is essential for chromosome stability. In most organisms, the DNA portion of the nucleoprotein complex consists of simple tandem DNA repeats with one strand guanine rich. The protein portion of the complex is less well understood. The experiments presented in two recent papers(1,2) represent different stages in the characterization of the telomeric DNA binding proteins. The first paper presents a structure‐function study of the Oxytricha telomeric DNA binding proteins and the second paper shows the identification and initial characterization of a telomeric DNA binding activity from Xenopus laevis. These two reports provided valuable information in understanding the structure and function of telomeres.
The origin, patterning and evolution of insect appendages
Authors: Williams Jim A. , Carroll Sean B.
Published: February 2005

The appendages of the adult fruit fly and other insects and Arthropods develop from secondary embryonic fields that form after the primary anterior/posterior and dorsal/ventral axes of the embryo have been determined. In Drosophila, the position and fate of the different fields formed within each segment are determined by genes acting along both embryonic axes, within individual segments, and within specific fields. Since the major architectural differences between most Arthropod classes and orders involve variations in the number, type and morphology of body appendages, the elucidation of the embryology and molecular genetics of the origin and patterning of insect limb fields may help to facilitate an understanding of both the mechanism of appendage formation and some of the major steps in the morphological evolution of the Arthropods. In this review, we will discuss recent studies that have advanced our understanding of both the origin and patterning of Drosophila leg and wing secondary fields. These results provide fresh insights into potentially general mechanisms of how body parts develop and evolve.
Human UDP‐glucuronosyl transferases: Chemical defence, jaundice and gene therapy
Authors: Brierley Catherine H. , Burchell Brian
Published: February 2005

Human UDP‐glucuronosyltransferases (UDPGTs) are a family of enzymes which detoxify many hundreds of compounds by their conjugation to glucuronic acid, rendering them both harmless and more water soluble, hence, excretable. The level of expression of each UDPGT isoform in the body is the result of interplay between temporal, tissue‐specific and environmental regulators. This complexity contributes to the difficulty in predicting the metabolic fate of compounds.

Genetic defects and polymorphisms affecting individual isoform activities have deleterious and potentially lethal effects, as exemplified by the severe hyperbilirubinaemia observed in Crigler‐Najjar Syndrome. Such severe genetic defects in bilirubin glucuronidation are obvious candidates for antenatal screening and gene therapy.
Protein tracking‐induced supercoiling of DNA: A tool to regulate DNA transactions in vivo?
Authors: Dröge Peter
Published: February 2005

An interplay between DNA‐dependent biological processes appears to be crucial for cell viability. At the molecular level, this interplay relies heavily on the communication between DNA‐bound proteins, which can be facilitated and controlled by the dynamic structure of double‐stranded DNA. Hence, DNA structural alterations are recognized as potential tools to transfer biological information over some distance within a genome. Until recently, however, direct evidence for DNA structural information as a mediator between cellular processes was lacking. This changed when the concept of transient waves of DNA supercoiling, induced by proteins tracking along the right‐handed DNA double helix, came into the limelight. Indeed, a number of observations now suggest that helix tracking‐induced DNA structural information might be exploited to participate in the regulation of a variety of DNA transactions in vivo.
α/β Barrel evolution and the modular assembly of enzymes: Emerging trends in the flavin oxidase/dehydrogenase family
Authors: Scrutton Nigel S.
Published: February 2005

α/β barrels have an ill‐defined origin. Evidence exists which favours their divergent evolution from a common ancestral barrel and convergent evolution to a stable fold. However, recent sequence and structural information for the flavin oxidase/dehydrogenase family of barrel enzymes indicate that sub‐families of α/β barrels have evolved divergently. The modular fusion of barrel domains with core structures from other gene families has also contributed to the evolution of related but catalytically distinct enzyme molecules within each sub‐family of the flavin oxidases/dehydrogenases. An analysis of the structures and sequences of the flavin oxidases/dehydrogenases has now enabled studies focusing on the evolutionary origins and modular assembly of this important family of proteins to be initiated.
The chromosome periphery during mitosis
Authors: Hernandez‐Verdun Danièle , Gautier Thierry
Published: February 2005

A complex structure, visible by electron microscopy, surrounds each chromosome during mitosis. The organization of this structure is distinct from that of the chromosomes and the cytoplasm. It forms a perichromosomal layer that can be isolated together with the chromosomes. This layer covers the chromosomes except in centromeric regions. The perichromosomal layer includes nuclear and nucleolar proteins as well as ribonucleoproteins (RNPs). The list of proteins and RNAs identified includes nuclear matrix proteins (perichromin, peripherin), nucleolar proteins (perichro‐monucleolin, Ki‐67 antigen, B23 protein, fibrillarin, p103, p52), ribosomal proteins (S1) and snRNAs (U3 RNAs). Only limited information is available about how and when the perichromosomal layer is formed. During early prophase, the proteins extend from the nucleoli towards the periphery of the nucleus. Thin cordon‐like structures reach the nuclear envelope delimiting areas in which chromosomes condense. At telophase, the proteins are associated with the part of the chromosomes remaining condensed and accumulate in newly formed nucleoli in regions where chromatin is already decondensed. The perichromosomal layer contains several different classes of proteins and RNPs and it has been attributed various roles: (1) in chromosome organization, (2) as a barrier around the chromosomes, (3) involvement in compartmentation of the cells in prophase and telophase and (4) a binding site for chromosomal passenger proteins necessary to the early process of nuclear assembly.
Reovirus protein σ1: From cell attachment to protein oligomerization and folding mechanisms
Authors: Lee Patrick W. K. , Leone Gustavo
Published: February 2005

The reovirus cell attachment protein σ1 is a lollipopshaped structure with the fibrous tail anchored to the virion. Since it interacts with the cell receptor, σ1 is a major determinant of reovirus infectivity and tissue tropism. Studies on its structure‐function relationships have been facilitated by the fact that protein σ1 produced in any expression system is capable of binding to cell receptors. The use of site‐specific and deletion mutants has led to the identification and characterization of its virion anchorage and receptor binding domains. Studies on the oligomeric status of σ1 have revealed that σ1 is a homotrimer and that two independent trimerization events at different loci (the N‐ and C‐terminal halves, respectively) of the protein, are involved in its generation. This also accounts for a clearly demonstrable dominant negative effect by a mutant subunit in a wild‐type/mutant σ1 heterotrimer. Current efforts are focused on the involvement of chaperones in the generation of σ1 and on events that take place upon σ1 binding to the cell receptor. Protein σ1 has therefore become an excellent model system for the study of both virus attachment and protein oligomerization and folding mechanisms.
Structural and functional properties of the evolutionarily ancient Y‐box family of nucleic acid binding proteins
Authors: Wolffe Alan P.
Published: February 2005

The Y‐box proteins are the most evolutionarily conserved nucleic acid binding proteins yet defined in bacteria, plants and animals. The central nucleic acid binding domain of the vertebrate proteins is 43% identical to a 70‐amino‐acid‐long protein (CS7.4) from E. coli. The structure of this domain consists of an antiparallel fivestranded β‐barrel that recognizes both DNA and RNA. The diverse biological roles of these Y‐box proteins range from the control of the E. coli cold‐shock stress response to the translational masking of messenger RNA in vertebrate gametes. This review discusses the organization of the prokaryotic and eukaryotic Y‐box proteins, how they interact with nucleic acids, and their biological roles, both proven and potential.
Genes and genomes: Sequencing 5‐methylcytosine residues in genomic DNA
Authors: Grigg Geoffrey , Clark Susan
Published: February 2005

To analyse the biological role of 5‐methylation of cytosine residues in DNA requires precise and efficient methods for detecting individual 5‐methylcytosines (5‐MeCs) in genomic DNA. The methods developed over the past decade rely on either differential enzymatic or chemical cleavage of DNA, or more recently on differential sensitivity to chemical conversion of one base to another. The most commonly used methods for studying the methylation profile of DNA, including the bisulphite base‐conversion method, are reviewed.
Mechanics of myosin motor: Force and step size
Authors: Jiang Ming Ya , Sheetz Michael P.
Published: February 2005

How motor proteins induce mechanical movement at the molecular level has been a focus of biophysicists for a long time. While the whole picture is yet to be completely revealed, recent developments in looking at nanometer‐scale movement with millisecond‐time resolution driven by single motors have revealed important new details about the moving step size and amount of force generated per molecule.
Salmonella: Now you see it, now you don't
Authors: Stein Murry A. , Mills Scott D. , Finlay B. Brett
Published: February 2005

Diseases caused by Salmonella species are characterized by bacterial invasion of host cells. Salmonella invasion requires a genetic locus (inv) with homology to bacterial systems involved in specific protein export and organelle assembly. Until recently, the actual Salmonella invasion factors exported or assembled by the inv system remained unidentified. It now appears that Salmonella produces novel appendages upon contact with host cells. These appendages are transient, appearing and disappearing rapidly from the bacterial surface. Appendages are altered in strains unable to invade due to mutations within the inv/spa locus. Therefore, a role for the invasion locus has been identified, providing another example of bacterial pathogens responding to signals provided by the host cell surface.
Phosphatidylinositol 3‐kinase
Authors: Kapeller Rosana , Cantley Lewis C.
Published: February 2005

Currently, a central question in biology is how signals from the cell surface modulate intracellular processes. In recent years phosphoinositides have been shown to play a key role in signal transduction. Two phosphoinositide pathways have been characterized, to date. In the canonical phosphoinositide turnover pathway, activation of phosphatidylinositol‐specific phospholipase C results in the hydrolysis of phosphatidylinositol 4,5‐bisphospate and the generation of two second messengers, inositol 1,4,5‐trisphosphate and diacylglycerol. The 3‐phosphoinositide pathway involves protein‐tyrosine kinase‐mediated recruitment and activation of phosphatidylinositol 3‐kinase, resulting in the production of phosphatidylinositol 3,4‐bisphosphate and phosphatidylinositol 3,4,5‐trisphosphate. The 3‐phosphoinositides are not substrates of any known phospholipase C, are not components of the canonical phosphoinositide turnover pathway, and may themselves act as intracellular mediators. The 3‐phosphoinositide pathway has been implicated in growth factor‐dependent mitogenesis, membrane ruffling and glucose uptake. Furthermore the homology of the yeast vps34 with the mammalian phosphatidylinositol 3‐kinase has suggested a role for this pathway in vesicular trafficking.

In this review the different mechanisms employed by protein‐tyrosine kinases to activate phosphatidylinositol 3‐kinase, and its involvement in the signaling cascade initiated by tyrosine phosphorylation, are examined.
Molecular biology of embryonic development: How far have we come in the last ten years?
Authors: Davidson Eric H.
Published: February 2005

The successes of molecular developmental biology over the last ten years have been particularly impressive in those directions favored by its major paradigms. New technologies have both guided and been guided by the progress of the field. I review briefly some of the major insights into embryonic development that have derived from research in four specific areas: early embryogenesis of various forms; “pattern formation”; evolutionary conservation of regulatory elements; and spatial mechanisms of gene regulation. There remain many major problem areas, some of which may require new orientations to solve.
Gene targeting in the mouse
Authors: Melton David W.
Published: February 2005

Mice with alterations to specific endogenous genes can be produced by gene targeting in embryonic stem cells. The field has developed rapidly over the past decade, so that large numbers of mice with different gene deficiencies have been generated. Knockout mice provide an ideal opportunity to analyse the function of individual mammalian genes and to model a range of human inherited disorders. This powerful approach has also identified numerous examples of gene redundancy and has highlighted the need to consider metabolic differences between man and mouse in disease modelling. More sophisticated gene‐targeting methods are now being used to introduce subtle gene alterations. In the future, more refined genetic analysis and genome, rather than individual gene, alterations will be achieved by incorporating site‐specific recombination into targeting strategies. Gene targeting could also make a contribution to improved protocols for gene therapy.
Tensin: A potential link between the cytoskeleton and signal transduction
Authors: Lo Su Hao , Weisberg Ellen , Chen Lan Bo
Published: February 2005

Cytoskeletal proteins provide the structural foundation that allows cells to exist in a highly organized manner. Recent evidence suggests that certain cytoskeletal proteins not only maintain structural integrity, but might also be associated with signal transduction and suppression of tumorigenesis. Since the time of the discovery of tensin, a fair amount of data has been gathered which supports the notion that tensin is one such protein possessing these characteristics. In this review, we discuss recent studies that: (1) elucidate a role for tensin in maintenance of cellular structure and signal transduction; (2) implicate tensin as the anchor for actin filaments at the focal adhesion; (3) describe the phosphorylation of tensin; (4) describe potential targets for its Src homology region 2 domain; (5) describe the association between tensin and the nuclear protein p130; and (6) demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential.
DNA damage tolerance, mismatch repair and genome instability
Authors: Karran P. , Bignami M.
Published: February 2005

DNA mismatch repair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6‐methylguanine and 6‐thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a consequence of this defect. Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatch repair proteins that are causally related to these cancers.
The tails of survival curves
Authors: Smith David W. E.
Published: February 2005

This article focuses on the occasional individuals of many species that live longer than is usual for their populations – here called longevity outliers. They appear to be exceptions to the usual patterns of mortality rates that increase with age. There is no model of survivorship that accommodates all of these individuals. They are less vulnerable to the usual causes of death than most in their populations. There are hints of genetically based mechanisms in the form of life‐prolonging genes in invertebrates and genetic resistance to fatal diseases in higher organisms. The reasons why longevity outliers ultimately die are not known. Based on well‐established trends, I predict that there will be many more humans reaching very old ages in the next century.
Nuclear/growth factors
Authors: Prochiantz A. , Théodore L.
Published: February 2005

The now classical model for cell‐cell communication espouses that information travels between cells in the form of molecules that bind specific cell‐surface receptors and trigger signal‐transducing mechanisms that eventually lead to transcriptional modifications. Here we gather the available information suggesting that some growth factors may also act by interfering directly with gene transcription, following their internalization and nuclear translocation. Among these factors are bona fide growth factors such as Fibroblast Growth Factor‐1 and ‐2 and Schwannoma Derived Growth Factor, for which internalization and nuclear translocation have been demonstrated. Conversely, we propose that some isoforms of nuclear factors of the homeoprotein family could pass from cell to cell. The implications of the model are presented in the context of the specificity of cellular interactions.
Illuminating plant development
Authors: Duckett Catherine M. , Gray John C.
Published: February 2005

Throughout 1994 remarkable progress was made with molecular and genetic studies on signal transduction pathways of photomorphogenesis, the lightdependent development of plants. Analysis of Arabidopsis DET and COP genes suggests that they are involved in suppression of photomorphogenic development in the dark and that this is then reversed by light. Studies with COP1 indicate that this is achieved by redistribution of COP1 from the nucleus, in the dark, to the cytosol in the light(1). Overexpression of COP1 in the light, however, was able to partially suppress photomorphogenic development, confirming its role as a light‐inactivatable repressor(2). Evidence also suggests that some of the COP gene products may interact directly to form a large complex(3).
Surprising developments in the legume root nodule
Authors: Cook Douglas
Published: February 2005

Root nodule morphogenesis involves the induction of mitotic activity in otherwise quiescent root cortical cells, giving rise to the nodule primordium. One gene expressed during nodule initiation, ENOD40, has been implicated in nodule growth and/or differentiation(1,2). Interestingly, although the nucleotide sequence of ENOD40 genes from soybean(3,4) and Medicago(1,2) are highly homologous, they are unlikely to encode a similar protein product. In fact, a remarkable feature of these genes is their apparent lack of protein coding potential. Thus, ENOD40 is a member of the growing list of eukaryotic genes whose RNA product is implicated in control of cell growth and differentiation, the so called riboregulators(5).
The cryptic life style of adenoassociated virus
Authors: Berns Kenneth I. , Linden R. Michael
Published: February 2005

Although 80–90% of adults are seropositive for antibodies against the human parvovirus adeno‐associated virus (AAV), infection has not been associated with either symptoms or disease. In cell culture, AAV infection is not productive unless there is a coinfection with a helper virus, either adenovirus or any type of herpes virus; in the absence of a helper virus coinfection the viral genome is integrated into the genome, usually at a specific site on chromosome 19q13.3‐qter. The integrated genome can be activated and rescued by subsequent super infection by a helper virus. The high frequency of site‐specific integration by AAV and the lack of associated disease have encouraged the use of AAV as a vector for gene therapy. This review will focus on the molecular mechanisms involved in the establishment of, and rescue from, the latent state and their relevance to use of AAV as a vector.
The initiation of senescence and its relationship to embryonic cell differentiation
Authors: Rosenberger Robert F.
Published: February 2005

Mouse embryonic stem cells have an unlimited lifespan in cultures if they are prevented from differentiating. After differentiating, they produce cells which divide only a limited number of times. These changes seen in cultures parallel events that occur in the developing embryo, where immortal embryonic cells differentiate and produce mortal somatic ones. The data strongly suggest that differentiation initiates senescence, but this view entails additional assumptions in order to explain how the highly differentiated sexual gametes manage to remain potentially immortal. Cells differentiate by blocking expression from large parts of their genome and it is suggested that losses or gains of genetic totipotency determine cellular lifespans. Cells destined to be somatic do not regain totipotency and senesce, while germ‐line cells regain complete genome expression and immortality after meiosis and gamete fusions. Losses of genetic totipotency could induce senescence by lowering the levels of repair and maintenance enzymes.
The origin and function of the mammalian Y chromosome and Y‐borne genes – an evolving understanding
Authors: Graves Jennifer A. Marshall
Published: February 2005

Mammals have an XX:XY system of chromosomal sex determination in which a small heterochromatic Y controls male development. The Y contains the testis determining factor SRY, as well as several genes important in spermatogenesis. Comparative studies show that the Y was once homologous with the X, but has been progressively degraded, and now consists largely of repeated sequences as well as degraded copies of X linked genes. The small original X and Y have been enlarged by cycles of autosomal addition to one partner, recombination onto the other and continuing attrition of the compound Y. This addition–attrition hypothesis predicts that the pseudoautosomal region of the human X is merely the last relic of the latest addition. Genes (including SRY) on the conserved or added region of the Y evolved functions in male sex determination and differentiation distinct from the general functions of their X‐linked partners. Although the gonadogenesis pathway is highly conserved in vertebrates, its control has probably changed radically and rapidly in vertebrate – even mammalian – evolution.
The channels model of nuclear matrix structure
Authors: Razin Sergey V. , Gromova Irina I.
Published: February 2005

The specificity of eukaryotic DNA organization into loops fixed to the nuclear matrix/chromosomal scaffold has been studied for more than fifteen years. The results and conclusions of different authors remain, however, controversial. Recently, we have elaborated a new approach to the study of chromosomal DNA loops. Instead of characterizing loop basements (nuclear matrix DNA), we have concentrated our efforts on the characterization of individual loops after their excision by DNA topoisomerase II‐mediated DNA cleavage at matrix attachment sites. In this review the results of applying this mapping approach are compared with the results and conclusions from studies of nuclear matrix DNA. An attempt is also made to reconsider all data about the specificity of DNA interactions with the nuclear matrix and to suggest a model of spatial organization of the eukaryotic genome which resolves apparent contradictions between these data.
Origins of G1 arrest in senescent human fibroblasts
Authors: Stein Gretchen H. , Dulić Vjekoslav
Published: February 2005

Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are ararrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c‐fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin‐dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactivate the cell cycle machinery.
Nuclear organization: Uniting replication foci, chromatin domains and chromosome structure
Authors: Jackson Dean A.
Published: February 2005

In higher eukaryotes, ‘replication factories’ coordinate DNA synthesis within local clusters of chromatin domains. Recent experiments(1,2) have confirmed the complexity of these clusters and established that the organization of sites labelled during S phase persists throughout the cell cycle. This implies that domain clusters are critical elements of an hierarchy that is fundamental to both nuclear and chromosome structure.
In vivo biochemistry: Physical monitoring of recombination induced by site‐specific endonucleases
Authors: Haber James E.
Published: February 2005

The recombinational repair of chromosomal double‐strand breaks (DSBs) is of critical importance to all organisms, who devote considerable genetic resources to ensuring such repair is accomplished. In Saccharomyces cerevisiae, DSB‐mediated recombination can be initiated synchronously by the conditional expression of two site‐specific endonucleases, HO or I‐Scel. DNA undergoing recombination can then be extracted at intervals and analyzed. Recombination initiated by meiotic‐specific DSBs can be followed in a similar fashion. This type of ‘in vivo biochemistry’ has been used to describe several discrete steps in two different homologous recombination pathways: gene conversion and single‐strand annealing. The roles of specific proteins during recombination can be established by examining DNA in strains deleted for the corresponding gene. These same approaches are now becoming available for the study of recombination in both higher plants and animals. Physical monitoring can also be used to analyze nonhomologous recombination events, whose mechanisms appear to be conserved from yeast to mammals.
Physiological and pathological interrelationships of amyloid β peptide and the amyloid precursor protein
Authors: Larner Andrew J.
Published: February 2005

Amyloid β peptide (βA4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may contribute to the cognitive decline that is a feature of these diseases. βA4 is a normal product of cell metabolism, derived from the amyloid precursor protein (APP), but the biological functions of these molecules are not fully known. A hypothetical, descriptive model of the biological interrelationships between βA4 and APP is presented. APPS, the soluble form of APP, which is released at the neuronal surface, and βA4 are envisaged as physiological ligands which have reciprocal paracrine effects on neuronal growth and neurite extension. Differential expression of these factors, manifest as changes in the APPS:βA4 ratio, may therefore have growth‐promoting or growth‐inhibiting effects on neurons. These effects may be mediated through separate cell‐surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negative feedback loops. Disturbances of these control mechanisms may permit pathological overproduction, and hence accumulation, of βA4. Such a model may also have therapeutic implications.
Tag team specification of a neural precursor in the Drosophila embryonic central nervous system
Authors: Skeath James B.
Published: February 2005

The development of vertebrate and invertebrate nervous systems requires the production of thousands to millions of uniquely specified neurons from progenitor neural stem cells. A central question focuses on the elucidation of the developmental mechanisms that function within neural stem cell lineages to impart unique identities to neurons. A recent report(1) details the roles that two genes, pdm‐1 and pdm‐2, play within an identified neural stem cell lineage in the Drosophila embryonic central nervous system. The results show that pdm‐1 and pdm‐2 are coexpressed in an identified neural precursor and function redundantly to specify the fate of this cell. As such this report offers an initial view of the genetic programs that create neural diversity.
The anterior‐posterior and dorsalventral axes have a common origin in Drosophila melanogaster
Authors: Munn Kirsteen , Steward Ruth
Published: February 2005

The mechanisms governing anterior‐posterior and dorsal‐ventral polarity in Drosophila melanogaster had previously been considered as independent processes. However, two papers(1,2) now reveal that both axes are initiated during oogenesis by the same pathway, and also clearly demonstrate that one is dependent on the other.
Melanoma formation in xiphophorus: A model system for the role of receptor tyrosine kinases in tumorigenesis
Authors: Malitschek Barbara , Förnzler Dorothee , Schartl Manfred
Published: February 2005

Cancer is one of the most frequent fatal human diseases. It is a genetic disease, and molecular analysis of the genes involved revealed that they belong to several distinct classes of molecules, one of which is the receptor tyrosine kinases. Neoplastic transformation is regarded as the result of a multistep process and, in most cases, it is hard to evaluate what the initial events in tumor formation are. What makes it difficult to approach this question is the paucity of animal models for tumorigenesis allowing investigation of the mechanisms leading to uncontrolled cell proliferation. Melanoma formation in Xiphophorus is one of these model systems. Here, overexpression and activation of a receptor tyrosine kinase causes neoplastic transformation of pigment cells. Xiphophorus provides all the advantages of a well‐characterised genetic system. In addition, some crucial components of the transformation pathway have been identified at the molecular level. As a vertebrate, Xiphophorus might serve as a model system to aid understanding, in more general terms, of the mechanisms of tumorigenesis in human diseases.
Surrogate cells or trojan horses. The discovery of liposomes
Authors: Bangham Alec D.
Published: February 2005

An autobiographical account of the liposome, from the perplexities of a blood smear to the growth of a multi‐million pound business.
Src and the control of cell division
Authors: Taylor Stephen J. , Shalloway David
Published: February 2005

The finely tuned mechanisms that control cell cycle progression go awry in cancer, pointing to proto‐oncogene products as important players in cell‐cycle regulation. One such proto‐oncoprotein, c‐Src, has previously been directly implicated, based on its requirement for growth factor‐stimulated DNA synthesis. Roche et al.(1) have now shown that c‐Src or its close relatives are also required for cell division to occur. The demonstration of essential functions for the Src family at multiple points in the cell cycle raises important questions about the normal and transforming activities of these and other proto‐oncoproteins.
How do single homeotic genes control multiple segment identities?
Authors: Duncan Ian
Published: February 2005

Each of the homeotic genes of the bithorax complex of Drosophila defines the identities of more than one body segment. The mechanisms by which this occurs have been elusive. In a recent report, Castelli‐Gair and Akam(1) analyze in detail the control of parasegment 5 and parasegment 6 identities by the bithorax complex gene Ubx. Their results indicate that differences in the spatial and temporal expression patterns of Ubx are critical in determining differences between these parasegments. However, dose effects observed by others indicate that parasegment‐specific differences in the level of Ubx expression are also important. For the other BX‐C genes, parasegment‐specific expression of protein isoforms, or combinatorial control dependent on the expression patterns of other spatially restricted regulators, may also play a role.
Serial analysis of gene expression: ESTs get smaller
Authors: Adams Mark D.
Published: February 2005

Measuring gene expression on a global scale has been one of the vexing problems of cell biology. Velculescu et al.(1) recently proposed a system for identifying gene expression levels based on very short sequence tags – about nine base pairs – located at a specific site within a gene transcript. By coupling the strategy to current automated sequencing machines and the large expressed sequence tag databases, it should be possible to follow changes in gene expression for large numbers of genes economically and accurately.
Molecular mechanisms of anti‐inflammatory action of glucocorticoids
Authors: Cato Andrew C. B. , Wade Erik
Published: February 2005

Glucocorticoid hormones are effective in controlling inflammation, but the mechanisms that confer this action are largely unknown. Recent advances in this field have shown that both positive and negative regulation of gene expression are necessary for this process. The genes whose activity are modulated in the anti‐inflammatory process code for several cytokines, adhesion molecules and enzymes. Most of them do not carry a classical binding site for regulation by a glucocorticoid receptor, but have instead regulatory sequences for transcription factors such as AP‐1 or NF‐κ. This makes them unusual targets for glucocorticoid action and emphasizes the need for novel regulatory mechanisms. Recent studies describe an important contribution by protein‐protein interactions, in which several domains of the receptor participate; these studies provide a better understanding of the action of the receptor and offer opportunities for the design of steroidal compounds that could function more effectively as anti‐inflammatory drugs.
Tadpole competence and tissue‐specific temporal regulation of amphibian metamorphosis: Roles of thyroid hormone and its receptors
Authors: Shi Yun‐Bo , Wong J. , Puzianowska‐Kuznicka M. , Stolow M. A.
Published: February 2005

Amphibian metamorphosis is a post‐embryonic process that systematically transforms different tissues in a tadpole. Thyroid hormone plays a causative role in this complex process by inducing a cascade of gene regulation. While natural metamorphosis does not occur until endogenous thyroid hormone has been synthesized, tadpoles are competent to respond to exogenous thyroid hormone shortly after hatching. In addition, even though the metamorphic transitions of individual organs are all controlled by thyroid hormone, each occurs at distinct developmental stages. Recent molecular studies suggest that this competence of premetamorphic tadpoles to respond to the hormone and the developmental stage‐dependent regulation of tissue‐specific transformations are determined in part by the levels of thyroid hormone receptors and the concentrations of cellular free thyroid hormone. In addition, at least two genes, encoding a cytosolic thyroid hormone binding protein and a 5‐deiodinase, respectively, are likely to be critical players in regulating cellular free thyroid hormone concentrations. This review discusses how all of these molecuar components coordinate to induce amphibian metamorphosis in a correct spatial and temporal manner. These studies provde us with general clues as to how and why tissues become competent to respond to hormonal signals.
Segmentation (and eve) in very odd insect embryos
Authors: French Vernon
Published: February 2005

The formation of segments in the Drosophila early embryo is understood in greater detail than any other complex developmental process. Now, by studying other types of insect embryo, we can hope to deduce something of the ancestral mechanism of segmentation and the ways in which it has been modified in evolution. The parasitic wasp, Copidosoma floridanum, is spectacularly atypical of insects in that the small egg cell divides extensively, with no initial syncytial phase, and forms eventually some 2000 embryos(1). This process raises intriguing questions about the control of embryonic polarity and segmentation.
BMP‐1 and the astacin family of metalloproteinases: A potential link between the extracellular matrix, growth factors and pattern formation
Authors: Sarras Michael P.
Published: February 2005

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP‐1) have previously been linked to cell differentiation and pattern formation during development through a proposed role in the activation of latent growth factors of the TGF‐β superfamily. Recent finding(1) indicate that BMP‐1 is identical to pro‐collagen C‐proteinase, which is a metalloproteinase involved in extracellular matrix (ECM) formation. This observation suggests that a functional link may exist between astacin metalloproteinases, growth factors and cell differentiation and pattern formation during development. Taken together, current studies indicate that BMP‐1 and possibly other astacin metalloproteinases are multifunctional enzymes that act directly on growth factors and the ECM. In combination, these dual actions would have profound effects on developmental processes.
Plant cell enlargement and the action of expansins
Authors: Cosgrove Daniel J.
Published: February 2005

Plant cells are caged within a distended polymeric network (the cell wall), which enlarges by a process of stress relaxation and slippage (creep) of the polysaccharides that make up the load‐bearing network of the wall. Protein mediators of wall creep have recently been isolated and characterized. These proteins, called expansins, appear to disrupt the noncovalent adhesion of matrix polysaccharides to cellulose microfibrils, thereby permitting turgor‐driven wall enlargement. Expansin activity is specifically expressed in the growing tissues of dicotyledons and monocotyledons. Sequence analysis of cDNAs indicates that expansins are novel proteins, without previously known functional motifs. Comparison of expansin cDNAs from cucumber, pea, Arabidopsis and rice shows that the proteins are highly conserved in size and amino acid sequence. Phylogenetic analysis of expansin sequences suggests that this multigene family diverged before the evolution of angiosperms. Speculation is presented about the role of this gene family in plant development and evolution.