Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase‐dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to (...) G2/M checkpoint activation. Such DDR‐positive telomeres, and those that occur as part of the telomere‐dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR‐positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. (shrink)

Diatoms are important protists that generate one fifth of the oxygen produced annually on earth. These aquatic organisms likely derived from a secondary endosymbiosis event, and they display peculiar genomic and structural features that reflect their chimeric origin. Diatoms were one of the first models of cell division and these early studies revealed a range of interesting features including a unique acentriolar microtubule‐organising centre. Unfortunately, almost nothing is known at the molecular level, in contrast to the advances in other experimental (...) organisms. Recently the full genome sequences of two diatoms have been annotated and molecular tools have been developed. These resources offer new possibilities to re‐investigate the mechanisms of cell division in diatoms by recruiting information from more intensively studied organisms. A renaissance of the topic is further justified by the current interest in diatoms as a source of biofuels and for understanding massive diatom proliferation events in response to environmental stimuli. (shrink)

Within the last decade, the study of mitosis has evolved into a multidisciplinary science in which findings from fields as diverse as chromosome biology and cytoskeletal architecture have converged to present a more cohesive understanding of the complex events that occur when cells divide. The largest strides have been made in the identification and characterization of regulatory enzymes (kinases and phosphatases) that modulate mitotic activity, as well as a number of the proteins and structural components (spindle, chromosomes, nuclear envelope) (...) which carry out the mitotic instructions. One emerging theme appears to be that molecular signalling, which can involve modification of components (such as phosphorylation) or even their specific destruction, monitors the state of the mitotic cell at all stages. One of the major challenges for the future will be the identification of addititonal targets of the signalling machinery, as well as new regulatory components and their targets on the chromosomes, on the spindle, and at the cleavage furrow. (shrink)

A framework for understanding the complex movements of mitosis and meiosis has been provided by the recent discovery of microtubule motor proteins, required for the proper distribution of chromosomes or the structural integrity of the mitotic or meiotic spindle. Although overall features of mitosis and meiosis are often assumed to be similar in mechanism, it is now clear that they differ in several important aspects. These include spindle structure and assembly, and timing of chromosome segregation to opposite poles. (...) Here we review progress in the functional characterization of several newly identified microtubule motor proteins, emphasizing their possible roles in spindle structure and function. (shrink)

One of the profound changes in cellular morphology during mitosis is a massive alteration in the organization of microfilament cytoskeleton. It has been recently discovered that nonmuscle caldesmon, an actin and calmodulin binding microfilament‐associated protein of relative molecular mass Mr = 83000, is dissociated from microfilaments during mitosis, apparently as a consequence of mitosis‐specific phosphorylation. cdc2 kinase, which is a catalytic subunit of MPF (maturation or mitosis promoting factor), is found to be responsible for the (...) class='Hi'>mitosis‐specific phosphorylation of caldesmon. Because caldesmon is implicated in the regulation of actin myosin interactions and/or microfilament organization, these results suggest that cdc2 kinase directly affects microfilament re‐organization during mitosis. (shrink)

Many aspects of biology, such as population genetics and senescence, are predicated on identifying individuals and generations. Conventional demarcations of individuals and generations, such as physiological autonomy, unicellular bottlenecks, and alternation of generation, are rife with problems. Do physically separated cuttings or plant ramets constitute separate individuals or generations? Are chimaeras one or more individuals? To resolve these problems, Clarke : 321–361, 2012) proposed that individuals are circumscribed by mechanisms that constrain heritable variance in fitness. Simultaneously, Gorelick and Heng : (...) 1088–1098 2011) showed that sex constrains heritable variance Therefore, for eukaryotes, meiosis and karyogamy provide a consistent way to demarcate individuals and generations. Epigenetic reset associated with meiosis and karyogamy rejuvenates the next generation, but not the parent that engaged in the sex act. Wholesale epigenetic resets that probably only occur with meiosis and karyogamy imply that monozygotic twins are two different individuals, but apomictic progeny are diffuse parts of one disaggregated individual. Mitotic heritability circumscribes an individual, whereas meiotic heritability demarcates new individuals and generations. (shrink)

During mitosis, cells comprehensively restructure their interior to promote the faithful inheritance of DNA and cytoplasmic contents. In metazoans, this restructuring entails disassembly of the nuclear envelope, redistribution of its components into the endoplasmic reticulum (ER) and eventually nuclear envelope reassembly around the segregated chromosomes. The microtubule cytoskeleton has recently emerged as a critical regulator of mitotic nuclear envelope and ER dynamics. Microtubules and associated molecular motors tear open the nuclear envelope in prophase and remove nuclear envelope remnants from (...) chromatin. Additionally, two distinct mechanisms of microtubule‐based regulation of ER dynamics operate later in mitosis. First, association of the ER with microtubules is reduced, preventing invasion of ER into the spindle area, and second, organelle membrane is actively cleared from metaphase chromosomes. However, we are only beginning to understand the role of microtubules in shaping and distributing ER and other organelles during mitosis. (shrink)

The following is a report of a meeting of the British Society for Cell Biology on ‘The Cell Cycle’, at St Andrews University, 4‐6 April, 1989.

The nature of the forces that move chromosomes in mitosis is beginning to be revealed. The kinetochore, a specialized structure situated at the primary constriction of the chromosome, appears to translocate in both directions along the microtubules of the mitotic spindle. One or more members of the newly described families of microtubule motor molecules may power these movements. Microtubules of the mitotic spindle undergo rapid cycles of assembly and disassembly. These microtubule dynamics may contribute toward generating force and regulating (...) direction in chromosome movement. (shrink)

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. (shrink)

We describe here recent work on the molecular genetics of mitosis in the filamentous fungus Aspergillus nidulans. Aspergillus is one of three simple eukaryotes with powerful genetic systems that have been used to analyze mitosis. The modern molecular biological techniques available with this organism have made it possible to use mutations to identify genes and proteins that play an important role in mitosis. Three Aspergillus genes that affect mitosis are described. One gene, nimA, is specifically expressed (...) late in the cell cycle and codes for a putative protein kinase that induces mitosis, even in cells blocked in S‐phase. The second gene, bimG, codes for a putative phosphatase that interacts functionally with the nimA kinase. The third gene, bimE, codes for a protein that suppresses mitosis during interphase, apparently by keeping nimA turned off. None of these genes appear to be similar to any of the genes affecting mitosis that have been characterized in other eukaryotes, but rather appear to be elements of a system that prevents mitosis from occurring during interphase. (shrink)

The secretory pathway delivers proteins synthesized at the rough endoplasmic reticulum (RER) to various subcellular locations via the Golgi apparatus. Currently, efforts are focused on understanding the molecular machineries driving individual processes at the RER and Golgi that package, modify and transport proteins. However, studies are routinely performed using non‐dividing cells. This obscures the critical issue of how the secretory pathway is affected by cell division. Indeed, several studies have indicated that protein trafficking is down‐regulated during mitosis. Moreover, the (...) RER and Golgi apparatus exhibit gross reorganization in mitosis. Here I provide a relatively neglected perspective of how the mitotic cyclin‐dependent kinase (CDK1) could regulate various stages of the secretory pathway. I highlight several aspects of the mitotic control of protein trafficking that remain unresolved and suggest that further studies on how the mitotic CDK1 influences the secretory pathway are necessary to obtain a deeper understanding of protein transport. (shrink)

Immunofluorescent labelling demonstrates that human metaphase chromosomes contain hyperacetylated histone H4. With the exception of the inactive X chromosome in female cells, where the bulk of histone H4 is under‐acetylated, H4 hyperacetylation is non‐uniformly distributed along the chromosomes and clustered in cytologically resolvable chromatin domains that correspond, in general, with the R‐bands of conventional staining. The strongest immunolabelling is often found in T‐bands, the subset of intense R‐bands having the highest GC content. The majority of mapped genes also occurs in (...) R‐band regions, with the highest gene density in T‐bands. These observations are consistent with a model in which hyperacetylation of histone H4 marks the position of potentially active gene sequences on metaphase chromosomes. Since acetylation is maintained during mitosis, progeny cells receive an imprint of the histone H4 acetylation pattern that was present on the parental chromosomes before cell division. Histone acetylation could provide a mechanism for propagating cell memory, defined as the maintenance of committed states of gene expression through cell lineages. (shrink)

Cell cycle arrest in M phase can be induced by the failure of a single chromosome to attach properly to the mitotic spindle. The same cell cycle checkpoint mediates M phase arrest when cells are treated with drugs that either disrupt or hyperstabilize spindle microtubules. Study of yeast mutants that fail to arrest in the presence of microtubule disruptors identified a set of genes important in this checkpoint pathway. Two recent papers report the cloning of human and Xenopus homologues of (...) one of these yeast genes, called MAD2 (for mitotic arrest deficient‐2)(1,2). Introduction of antibodies to the MAD2 protein into living mammalian cells or Xenopus egg extracts abrogates the M phase arrest induced by microtubule inhibitors. This and other recent developments suggest a model for the M phase checkpoint in which unattached kinetochores inhibit the ubiquitination of proteins whose proteolysis is necessary for chromatid separation and exit from mitosis. (shrink)

Cell division is an universal process the aim of which is the equitable distribution of subcellular organelles from single cells to their daughters. The extraordinary accuracy with which the genetic material is partitioned requires a complex machinery involving many gene products. Genetic approaches can be used to identify the relevant components and processes, and mutational analysis of loci essential for cell division has been carried out in several eukaryotes, in particular fungi and mammalian cells in culture. Recently, this type of (...) analysis has been extended to Drosophila, an ideal eukaryote for genetic studies. We will review here the genetic dissection of mitosis in Drosophila melanogaster, discussing recent findings of interest and the methodological problems that have been encountered. (shrink)

Protein synthesis inhibitors prolong the half‐lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA‐specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates decline (...) drastically during a 1–2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half‐lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation. (shrink)

Mitotic entry and exit are switch‐like transitions that are driven by the activation and inactivation of Cdk1 and mitotic cyclins. This simple on/off reaction turns out to be a complex interplay of various reversible reactions, feedback loops, and thresholds that involve both the direct regulators of Cdk1 and its counteracting phosphatases. In this review, we summarize the interplay of the major components of the system and discuss how they work together to generate robustness, bistability, and irreversibility. We propose that it (...) may be beneficial to regard the entry and exit reactions as two separate reversible switches that are distinguished by differences in the state of phosphatase activity, mitotic proteolysis, and a dramatic rearrangement of cellular components after nuclear envelope breakdown, and discuss how the major Cdk1 activity thresholds could be determined for these transitions. (shrink)

The telomere is a functional domain of the chromosome, located at the extreme ends, and is essential for normal chromosome stability. Chromosomes lacking telomeres are inherited improperly, and mutations in the telomeric repeat sequences are thought to lead to senescence and possibly to cancer. The molecular mechanisms maintaining chromosomes by telomeres, however, have been unclear. Results recently reported by Kirk et al.(1) offer an insight into new telomerase function. They have identified a novel telomerase mutation that blocks sister chromatid separation (...) in mitosis. (shrink)

Movement and positional control of mitochondria and other organelles are coordinated with cell cycle progression in the budding yeast, Saccharomyces cerevisiae. Recent studies have revealed a checkpoint that inhibits cytokinesis when there are severe defects in mitochondrial inheritance. An established checkpoint signaling pathway, the mitotic exit network (MEN), participates in this process. Here, we describe mitochondrial motility during inheritance in budding yeast, emerging evidence for mitochondrial quality control during inheritance, and organelle inheritance checkpoints for mitochondria and other organelles.

Focal adhesions disassemble during mitosis, but surprisingly little is known about how these structures respond to other phases of the cell cycle. Three recent papers reveal unexpected results as they examine adhesions through the cell cycle. A biphasic response is detected where focal adhesions grow during S phase before disassembly begins early in G2. In M phase, activated integrins at the tips of retraction fibers anchor mitotic cells, but these adhesions lack the defining components of focal adhesions, such as (...) talin, paxillin, and zyxin. Re‐examining cell‐matrix adhesion reveals reticular adhesions, a new class of adhesion. These αVβ5 integrin‐mediated adhesions also lack conventional focal adhesion components and anchor mitotic cells to the extracellular matrix. As reviewed here, these studies present insight into how adhesion complexes vary through the cell cycle, and how unconventional adhesions maintain attachment during mitosis while providing spatial memory to guide daughter cell re‐spreading after cell division. (shrink)

Here we discuss a “chromosome separation checkpoint” that might regulate the anaphase‐telophase transition. The concept of cell cycle checkpoints was originally proposed to account for extrinsic control mechanisms that ensure the order of cell cycle events. Several checkpoints have been shown to regulate major cell cycle transitions, namely at G1‐S and G2‐M. At the onset of mitosis, the prophase‐prometaphase transition is controlled by several potential checkpoints, including the antephase checkpoint, while the spindle assembly checkpoint guards the metaphase‐anaphase transition. Our (...) hypothesis is based on the recently uncovered feedback control mechanism that delays chromosome decondensation and nuclear envelope reassembly until effective separation of sister chromatids during anaphase is achieved. A central player in this potential checkpoint is the establishment of a constitutive, midzone‐based Aurora B phosphorylation gradient that monitors the position of chromosomes along the spindle axis. We propose that this surveillance mechanism represents an additional step towards ensuring mitotic fidelity. (shrink)

Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin‐dependent kinase 1 (Cdk1)‐cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo‐cytoplasmic transport of critical cell cycle regulators such (...) as Cdk1‐cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo‐cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis. (shrink)

Chromosomes are not only carriers of the genetic material, but also actively regulate the assembly of complex intracellular architectures. During mitosis, chromosome‐induced microtubule polymerisation ensures spindle assembly in cells without centrosomes and plays a supportive role in centrosome‐containing cells. Chromosomal signals also mediate post‐mitotic nuclear envelope (NE) re‐formation. Recent studies using novel approaches to manipulate histones in oocytes, where functions can be analysed in the absence of transcription, have established that nucleosomes, but not DNA alone, mediate the chromosomal regulation (...) of spindle assembly and NE formation. Both processes require the generation of RanGTP by RCC1 recruited to nucleosomes but nucleosomes also acquire cell cycle stage specific regulators, Aurora B in mitosis and ELYS, the initiator of nuclear pore complex assembly, at mitotic exit. Here, we review the mechanisms by which nucleosomes control assembly and functions of the spindle and the NE, and discuss their implications for genome maintenance. (shrink)

Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non‐programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell division are (...) discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named “chronocrisis”) of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non‐programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted. (shrink)

Continuous poleward motion of microtubules in metazoan mitotic spindles has been fascinating generations of cell biologists over the last several decades. In human cells, this so‐called poleward flux was recently shown to be driven by the coordinated action of four mitotic kinesins. The sliding activities of kinesin‐5/EG5 and kinesin‐12/KIF15 are sequentially supported by kinesin‐7/CENP‐E at kinetochores and kinesin‐4/KIF4A on chromosome arms, with the individual contributions peaking during prometaphase and metaphase, respectively. Although recent data elucidate the molecular mechanism underlying this cellular (...) phenomenon, the functional roles of microtubule poleward flux during cell division remain largely elusive. Here, we discuss potential contribution of microtubule flux engine to various essential processes at different stages of mitosis. (shrink)

The origin of mitosis and the nuclear envelope were the pivotal processes in the evolutionary origin of the nucleus; they probably occurred in a wall‐less mutant bacterium that evolved a cytoskeleton and phagocytosis about 1500 million years ago. Principles of intracellular coevolution clarify their origin, as well as that of nucleosomes, spliceosomes, and the evolution of genome size.

Correct chromosome segregation in mitosis relies on chromosome biorientation, in which sister kinetochores attach to microtubules from opposite spindle poles prior to segregation. To establish biorientation, aberrant kinetochore–microtubule interactions must be resolved through the error correction process. During error correction, kinetochore–microtubule interactions are exchanged (swapped) if aberrant, but the exchange must stop when biorientation is established. In this article, we discuss recent findings in budding yeast, which have revealed fundamental molecular mechanisms promoting this “swap and stop” process for error (...) correction. Where relevant, we also compare the findings in budding yeast with mechanisms in higher eukaryotes. Evidence suggests that Aurora B kinase differentially regulates kinetochore attachments to the microtubule end and its lateral side and switches relative strength of the two kinetochore–microtubule attachment modes, which drives the exchange of kinetochore–microtubule interactions to resolve aberrant interactions. However, Aurora B kinase, recruited to centromeres and inner kinetochores, cannot reach its targets at kinetochore–microtubule interface when tension causes kinetochore stretching, which stops the kinetochore–microtubule exchange once biorientation is established. (shrink)

Entry into mitosis is driven by the activity of kinases, which phosphorylate over 7000 proteins on multiple sites. For cells to exit mitosis and segregate their genome correctly, these phosphorylations must be removed in a specific temporal order. This raises a critical and important question: how are specific phosphorylation sites on an individual protein removed? Traditionally, the temporal order of dephosphorylation was attributed to decreasing kinase activity. However, recent evidence in human cells has identified unique patterns of dephosphorylation (...) during mammalian mitotic exit that cannot be fully explained by the loss of kinase activity. This suggests that specificity is determined in part by phosphatases. In this review, we explore how the physicochemical properties of an individual phosphosite and its surrounding amino acids can affect interactions with a phosphatase. These positive and negative interactions in turn help determine the specific pattern of dephosphorylation required for correct mitotic exit. (shrink)

Segregation of chromosomes during mitosis requires the interaction of dynamic microtubules with the kinetochore, a large protein structure established on the centromere region of sister chromatids. The core microtubule‐binding activity of the kinetochore resides in the KMN network, an outer kinetochore complex. As part of the KMN network, the Ndc80 complex, which is composed of Ndc80, Nuf2, Spc24, and Spc25, is able to bind directly to microtubules and has the ability to track with depolymerizing microtubules to produce chromosome movement. (...) The Ndc80 complex binds directly to microtubules through a calponin homology domain and an unstructured tail in the N terminus of the Ndc80 protein. A recent flurry of papers has highlighted the importance of an internal loop region in Ndc80 in establishing end‐on attachment to microtubules. Here I discuss these recent findings that suggest that the Ndc80 internal loop functions as a binding site for proteins required for kinetochore‐microtubule interactions. (shrink)

Studies exploring how students learn and understand science processes such as diffusion and natural selection typically find that students provide misconceived explanations of how the patterns of such processes arise (such as why giraffes’ necks get longer over generations, or how ink dropped into water appears to “flow”). Instead of explaining the patterns of these processes as emerging from the collective interactions of all the agents (e.g., both the water and the ink molecules), students often explain the pattern as being (...) caused by controlling agents with intentional goals, as well as express a variety of many other misconceived notions. In this article, we provide a hypothesis for what constitutes a misconceived explanation; why misconceived explanations are so prevalent, robust, and resistant to instruction; and offer one approach of how they may be overcome. In particular, we hypothesize that students misunderstand many science processes because they rely on a generalized version of narrative schemas and scripts (referred to here as a Direct-causal Schema) to interpret them. For science processes that are sequential and stage-like, such as cycles of moon, circulation of blood, stages of mitosis, and photosynthesis, a Direct-causal Schema is adequate for correct understanding. However, for science processes that are non-sequential (or emergent), such as diffusion, natural selection, osmosis, and heat flow, using a Direct Schema to understand these processes will lead to robust misconceptions. Instead, a different type of general schema may be required to interpret non-sequential processes, which we refer to as an Emergent-causal Schema. We propose that students lack this Emergent Schema and teaching it to them may help them learn and understand emergent kinds of science processes such as diffusion. Our study found that directly teaching students this Emergent Schema led to increased learning of the process of diffusion. This article presents a fine-grained characterization of each type of Schema, our instructional intervention, the successes we have achieved, and the lessons we have learned. (shrink)

The genetic code appeared on Earth at the origin of life, and the codes of culture arrived almost four billion years later. For a long time it has been assumed that these are the only codes that exist in Nature, and if that were true we would have to conclude that codes are extraordinary exceptions that appeared only at the beginning and at the end of the history of life. In reality, various other organic codes have been discovered in the (...) past few decades and it is likely that more will come to light in the future. The existence of many organic codes in Nature is therefore an experimental fact, but also more than that. It is one of those facts that have extraordinary implications. In this book it is shown that the genetic code was a precondition for the origin of the first cells, the signal transduction codes divided the first cells into three primary kingdoms (Archaea, Bacteria and Eukarya), the splicing codes were instrumental to the origin of the eukaryotic nucleus, the histone code provided a new regulation system in eukaryotic genomes, and the cytoskeleton codes allowed the Eukarya to perform internal movements, including those of mitosis and meiosis. It is shown, furthermore, that organic codes had a key role in multicellular life, in particular in the origin of animals, the origin of mind and the origin of language. The great events of macroevolution, in other words, were associated with the appearance of new organic codes, and we can easily understand why. The reason is that a new code brings into existence something that has never existed before because it creates arbitrary associations, relationships that are not determined by physical necessity. Another outstanding implication is the fact that codes involve meaning and we need therefore to introduce in biology, with the standard methods of science, not only the concept of biological information but also that of biological meaning. The research on biological codes, in conclusion, is bringing to light new mechanisms in evolution and new fundamental concepts in science. This research is the field of Code Biology, the study of all codes of life, from the genetic code to the codes of culture, from the origin of life to the origin of man. (shrink)

This book tells the story of modern ethics, namely the story of a discourse that, after the Renaissance, went through a methodological revolution giving birth to Grotius’s and Pufendorf’s new science of natural law, leaving room for two centuries of explorations of the possible developments and implications of this new paradigm, up to the crisis of the Eighties of the eighteenth century, a crisis that carried a kind of mitosis, the act of birth of both basic paradigms of the (...) two following centuries: Kantian ethics and utilitarianism. The new science of natural law carried a fresh start for ethics, resulting from a mixture of the Old and the New. It was, as suggested by Schneewind, an attempt at rescuing the content of Scholastic and Stoic doctrines on a new methodological basis. The former was the claim of existence of objective and universal moral laws; the latter was the self-aware attempt at justifying a minimal kernel of such laws facing skeptical doubt. What Bentham and Kant did was precisely carrying this strategy further on, even if restructuring it each of them around one out of two alternative basic claims. The nineteenth- and twentieth-century critics of the Enlightenment attacked both not on their alleged failure in carrying out their own projects, but precisely on having adopted Grotius’s and Pufendorf’s project. What counter-enlightenment has been unable to spell out is which alternative project could be carried out facing the modern condition of pluralism, while on the contrary, if we takes a closer look at developments in twentieth-century ethics or at on-going discussions on practical issues, we might feel inclined to believe that Grotius’s and Pufendorf’s project is as up-to-date as ever. -/- Table of Contents -/- Preface I. Fathers of the Reformation and Schoolmen 1.1. Luther: passive justice and the good deeds; 1.2. Calvin: voluntarism and predestination; 1.3. Baroque Scholasticism; 1.4. Casuistry and Institutiones morales -/- II Neo-Platonists, neo-Stoics, neo-Sceptics 2.1. Aristotelian, neo-Platonic, neo-Epicurean and neo-Cynic Humanists; 2.2. Oeconomica and the art of living; 2.3. Neo-Stoics; 2.4. Neo-Sceptics; 2.5. Moralistic literature -/- III Neo-Augustinians 3.l. The Jansenists on natura lapsa, sufficient grace, pure love; 3.2. Nicole on the impossibility of self-knowledge; 3.3. Nicole on self-love and charity; 3.4. Nicole against civic virtue, for Christian civility; 3.5. Malebranche on general laws and necessary evil; 3.6. Malebranche on Neo-Augustinianism and Platonism. -/- IV Grotius, Pufendorf and the new moral science 4.1. Grotius against Aristotle and the sceptics; 4.2. Mersenne and Gassendi; 4.3. Descartes on ethics as the last branch of philosophy’s tree; 4.4. Hobbes on scepticism and the new moral science; 4.5. Spinoza on the new moral science as a descriptive science;4.6. Locke on voluntarism and probabilism; 4.7. Pufendorf on natural law as an exact science; 4.8. Pufendorf on physical and moral entities; 10. Pufendorf on self-preservation -/- V The empiricist version of the new moral science: from Cumberland to Paley 5.1. Cumberland against Hobbesian voluntarism; 5.2. Cumberland and theological consequentialism; 5.3. Cumberland on universal benevolence and self-love; 5.4. Shaftesbury on the moral sense; 5.5. Hutcheson on natural law and moral faculties; 5.6. Gay, Brown, Paley and theological consequentialism. -/- VI The rationalist version of the new moral science: from Cudworth to Price 6.1. The Cambridge Platonists; 6.2. Shaftesbury on the moral sense; 6.3. Butler and a third way between voluntarism and scepticism; 6.4. Price and the rational character of moral truths; -/- VII Leibniz’s compromise between the new moral science and Aristotelianism 1.Leibniz against voluntarism; 2.Leibniz against the division between the physical and the moral good; 3.Leibniz on la place d’autrui and theological consequentialism; 4.Thomasius, Wolff, Crusius -/- VIII French eighteenth-century philosophers without the new moral science 8.1. The genealogy of our ideas of virtue and vice; 8.2. Maupertuis and moral arithmetic 8.3. The philosophes and the harmony of interests; 8.4. Rousseau on corruption, self-love, and virtue; 8.5. Sade on the merits of vice -/- IX Experimental moral science: Hume and Adam Smith 9.1. Mandeville’s paradox; 9.2. Hutcheson on the law of nature and moral faculties; 9.3. Hume on experimental moral philosophy and the intermediate principles; 9.4. Hume’s Law; 9.5. Hume on the fellow-feeling; 9.6. Hume on natural and artificial virtues and disinterested pleasure for utility; 9.7. Adam Smith’s anti-realist metaethics; 9.8. Adam Smith on self-deception and the paradox of happiness; 9.9. Adam Smith on sympathy and the impartial spectator; 9.10. Adam Smith on the twofold criterion for moral judgement and its paradox; 9.11. Reid on the refutation of scepticism and the self-evidence of duty -/- X Kantian ethics 10.1. Kantian metaethics: moral epistemology; 10.2. Kantian metaethics: moral ontology; 10.3. Kantian metaethics: moral psychology; 10.4. Kantian normative ethics; 10.5. Kant on the impracticability of applied ethics; 10.6. Kantian moral anthropology; 10.7. Civilisation and moralisation; 10.8. Theology on a moral basis and the origins of evil; 10.9. Fichte and the transformation of theoretical philosophy into practical philosophy XI Bentham and utilitarianism 11.1. Bentham’s linguistic theory; 11.2. Bentham’s moral ontology, psychology, and theory of action; 11.3. The principle of greatest happiness; 11.4. The critique of religious ethics; 11.5. The new morality; 11.6. Interest and duty; 11.7. Virtues; 11.8. Private ethics and legislation -/- XII Followers of the Enlightenment: liberal Judaism and Liberal Theology 12.1. Mendelssohn; 12.2. Salomon Maimon; 12.3. Haskalā and liberal Judaism; 12.4. Liberal Theology. -/- XIII Counter-Enlighteners 13.1.Romanticism and the fulfilment of individuality as the Summum Bonum; 13.2. Hegel on history as the making of liberty; 13.3. Hegel on the unhappy consciousness and the beautiful soul; 13.4. Hegel on Morality and Sittlichkeit; 13.5. Marx on ideology, alienation, and praxis; 13.6. Schopenhauer on compassion; 13.7. Kierkegaard on faith beyond ethics. -/- XIV Followers of the Enlightenment: intuitionists and utilitarian 14.1 Whewell‘s criticism of utilitarianism; 14.2 Whewell on morality and the philosophy of morality; 14.3 Whewell on the Supreme Norm; 14.4 Whewell on the conflict between duties; 14.5 Mill and the proof of the principle of utility; 14.6 Mill’s eudemonistic utilitarianism; 14.7 Mill on rules -/- XV Followers of the Enlightenment: neo-Kantians and positivists 15.1. French spiritualism; 15.2. Neo-Kantians: the Marburg school; 15.3. Neo-Kantians: the Marburg school; 15.4. Comte’s positivism and the invention of altruism; 15.5. Social Darwinism; 15.6. Wundt and an ethic of humankind -/- XVI Post-enlighteners: Sidgwick 16.1. Criticism of intuitionism; 16.2. On ethical egoism; 16.3. Criticism of utilitarianism -/- XVII Post-enlighteners: Durkheim 17.1. Sociology as physics of customs; 17.2. Morality as physics of customs and as practical science; 17.3. On Kantian ethics and utilitarianism; 17.4. The variability of moralities;17.5. Social solidarity as end and justification of morality; 17.6. Secular morality as “sociodicy”; XVIII Post-enlighteners: Nietzsche 18.1. On the Dionysian; 18.2. On the deconstruction of the world of values 18.3 On the twofold genealogy of moralities; 18.4. On ascetics and nihilism; 18.5. Normative ethics of self-fulfilment -/- Bibliography / Index of names / Index of concepts -/- . (shrink)

Eukaryotic genomes are packaged into a nucleoprotein complex known as chromatin. The term was introduced in 1879 by German cytologist Walther Flemming. While observing the processes of mitosis in a light microscope, Flemming coined the term to describe the easily stainable threads in the nucleus. He predicted that it would not have a long life: “The word chromatin may serve until its chemical nature is known, and meanwhile stands for that substance in the cell nucleus which is readily stained”. (...) However, Flemming’s prediction did not come true. Although the chemical nature of chromatin—a complex of nucleic acid and proteins—was already elucidated at the end of the 19th century, the.. (shrink)

SummaryMis‐regulation (e.g. overproduction) of the human Ndc80/Hec1 outer kinetochore protein has been associated with aneuploidy and tumourigenesis, but the genetic basis and underlying mechanisms of this phenomenon remain poorly understood. Recent studies have identified the ubiquitous Ndc80 internal loop as a protein‐protein interaction platform. Binding partners include the Ska complex, the replication licensing factor Cdt1, the Dam1 complex, TACC‐TOG microtubule‐associated proteins (MAPs) and kinesin motors. We review the field and propose that the overproduction of Ndc80 may unfavourably absorb these interactors (...) through the internal loop domain and lead to a change in the equilibrium of MAPs and motors in the cells. This sequestration will disrupt microtubule dynamics and the proper segregation of chromosomes in mitosis, leading to aneuploid formation. Further investigation of Ndc80 internal loop‐MAPs interactions will bring new insights into their roles in kinetochore‐microtubule attachment and tumourigenesis. (shrink)

Association between sister chromatids is essential for their attachment and segregation to opposite poles of the spindle in mitosis and meiosis II. Sister‐chromatid cohesion is also likely to be involved in linking homologous chromosomes together in meiosis I. Cytological observations provide evidence that attachment between sister chromatids is different in meiosis and mitosis and suggest that cohesion between the chromatid arms may differ mechanistically from that at the centromere. The physical nature of cohesion is addressed, and proteins that (...) are candidates for holding sister chromatids together are discussed. Dissolution of sister‐chromatid cohesion must be regulated precisely, and potential mechanisms to release cohesion are presented. (shrink)

Kinetochores can form and be maintained on DNA sequences that are normally non‐centromeric. The existence of these so‐called neo‐centromeres has posed the problem as to the nature of the epigenetic mechanisms that maintain the centromere. Here we highlight results that indicate that the amount of CENP‐A at human centromeres is tightly regulated. It is also known that kinetochore assembly requires sister chromatid cohesion at mitosis. We therefore suggest that separation or stretching between the sister chromatids at metaphase reciprocally determines (...) the amount of centromere assembly in the subsequent interphase. This reciprocal relationship forms the basis of a negative feedback loop that could precisely control the amount of CENP‐A and faithfully maintain the presence of a kinetochore over many cell divisions. We describe how the feedback loop would work, propose how it could be tested experimentally and suggest possible components of its mechanism. (shrink)

DNA double‐strand breaks (DSBs) are extremely hazardous lesions for all DNA‐bearing organisms and the mechanisms of DSB repair are highly conserved. In the eukaryotic mitotic cell cycle, DSBs are often present following DNA replication while, in meiosis, hundreds of DSBs are generated as a prelude to the reshuffling of the maternally and paternally derived genomes. In both cases, the DSBs are repaired by a process called homologous recombinational repair (HRR), which utilises an intact DNA molecule as the repair template. Mitotic (...) and meiotic HRR are managed by ‘checkpoints’ that inhibit cell division until DSB repair is complete. Here we attempt to summarise the substantial recent progress in understanding the checkpoint management of HRR in mitosis (focussing mainly on mammals) and then go on to use this information as a framework for understanding the presumed checkpoint management of HRR in mammalian meiosis. BioEssays 29:974–986, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Mitotic spindles constitute the machinery responsible for equidistribution of the genetic material into each daughter cell during cell division. They are transient and hence quite labile structures, changing their morphology even while performing their function. Biochemical, immunological and genetic analyses of mitotic cells have allowed us to identify a variety of molecules that are recruited to form the spindle at the onset of mitosis. Evaluation of the roles of these molecules in both the formation and in the dynamics of (...) spindle microtubules should be important for understanding the molecular basis of mitosis and its regulation. We have recently identified a novel mitosis‐specific microtubule‐associated protein (MAP) using a monoclonal antibody probe raised against the mitotic spindles isolated from cultured mammalian cells. This 95/105 kDa antigen represents a unique component of the spindle distinct from any of the other MAPs reported so far. Antibody microinjection resulted in mitotic inhibition in a stage‐specific and dosedependent manner, indicating that the protein is an essential spindle component. (shrink)

The quantitative study of regulation of cell growth and proliferation began with the development of the technique for monolayer culture of vertebrate cells in the late 1960s. The basic parameters were defined in the early physiological studies, which continued through the next decade. These included specific and non-specific growth factors and the requirement for continuous exposure to such factors through most of the G1 period for progression to S. In the course of this work, the diversity of biochemical responses and (...) the critical role of increased protein synthesis and accumulation for the onset of DNA synthesis were elucidated. In particular, a central role of free cytosolic Mg2+ in direct regulation of protein synthesis and in ancillary processes as a response to membrane perturbation was established. Eventually, the physiological era was superseded by the molecular era beginning in the 1980s. This work focussed on specific receptors for growth factors that entrained a protein kinase cascade, which terminated in a higher frequency of initiation of protein synthesis. However, the molecular studies virtually ignored the key results of the physiological era. Recent studies of the penultimate molecular steps in the regulatory pathway of protein synthesis, however, have supported a model of growth regulation involving membrane perturbation and MgATP2− concentration, results that integrate the findings of the physiological and molecular eras. The resulting relatively simple “membrane, magnesium mitosis” (MMM) model of proliferation control can explain the seeming paradox of the variety of specific and non-specific growth-enhancing treatments that are mediated by the plasma membrane and which bring about a shared, complex but coordinated growth response that drives cell proliferation. BioEssays 27:311–320, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Type II DNA topoisomerase activity is required to change DNA topology. It is important in the relaxation of DNA supercoils generated by cellular processes, such as transcription and replication, and it is essential for the condensation of chromosomes and their segregation during mitosis. In mammals this activity is derived from at least two isoforms, termed DNA topoisomerase IIα and β. The α isoform is involved in chromosome condensation and segregation, whereas the role of the β isoform is not yet (...) clear. DNA topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the last 10 years. BioEssays 20:215–226, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

Despite advances in treatments over the last decades, a uniformly reliable and free of side effects therapy of human cancers remains to be achieved. During chromosome replication, a premature halt of two converging DNA replication forks would cause incomplete replication and a cytotoxic chromosome nondisjunction during mitosis. In contrast to normal cells, most cancer cells bear numerous DNA deletions. A homozygous deletion permanently marks a cell and its descendants. Here, we propose an approach to cancer therapy in which a (...) pair of sequence‐specific roadblocks is placed solely at two cancer‐confined deletion sites that are located ahead of two converging replication forks. We describe this method, termed “replication blocks specific for deletions” (RBSD), and another deletions‐based approach as well. RBSD can be expanded by placing pairs of replication roadblocks on several different chromosomes. The resulting simultaneous nondisjunctions of these chromosomes in cancer cells would further increase the cancer‐specific toxicity of RBSD. (shrink)

It has been recently demonstrated that yeast cells are able to partially regress chromosome segregation in telophase as a response to DNA double‐strand breaks (DSBs), likely to find a donor sequence for homology‐directed repair (HDR). This regression challenges the traditional concept that establishes anaphase events as irreversible, hence opening a new field of research in cell biology. Here, the nature of this new behavior in yeast is summarized and the underlying mechanisms are speculated about. It is also discussed whether it (...) can be reproduced in other eukaryotes. Overall, this work brings forwards the need of understanding how cells attempt to repair DSBs when transiting the latest stages of mitosis, i.e., anaphase and telophase. (shrink)

Type II DNA topoisomerase activity is required to change DNA topology. It is important in the relaxation of DNA supercoils generated by cellular processes, such as transcription and replication, and it is essential for the condensation of chromosomes and their segregation during mitosis. In mammals this activity is derived from at least two isoforms, termed DNA topoisomerase IIα and β. The α isoform is involved in chromosome condensation and segregation, whereas the role of the β isoform is not yet (...) clear. DNA topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the last 10 years. BioEssays 20:215–226, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

Dependency relationships within the cell cycle allow cells to arrest the cycle reversibly in response to agents or conditions that interfere with specific aspects of its normal progression. In addition, overlapping pathways exist which also arrest the cell cycle in response to DNA damage. Collectively, these control mechanisms have become known as checkpoints. Analysis of checkpoints is facilitated by the fact that dependency relationships within the cell cycle, such as the dependency of mitosis on the completion of DNA synthesis, (...) and the DNA damage checkpoint can be separated genetically. In fission yeast, Schizosaccharomyces pombe, the dependency of mitosis on prior completion of DNA synthesis is mediated through tyrosine‐15 phosphorylation of the ubiquitous mitotic regulator p34cdc2. In contrast, the arrest of mitosis caused by DNA damage acts through a separate mechanism that appears to be independent of tyrosine‐15 phosphorylation. Despite these distinct interactions with the mitotic machinery, the majority of fission yeast mutants that are deficient in mitotic arrest after DNA damage are also unable to respond to inhibition of DNA synthesis. In this essay we survey the current knowledge concerning feedback controls and checkpoints within fission yeast and relate this to information derived from other systems. (shrink)

Eukaryotic chromosomes undergo dramatic changes and movements during mitosis. These include the individualization and compaction of the two copies of replicated chromosomes (the sister chromatids) and their subsequent segregation to the daughter cells. Two multisubunit protein complexes termed ‘cohesin’ and ‘condensin’, both composed of SMC (Structural Maintenance of Chromosomes) and kleisin subunits, have emerged as crucial players in these processes. Cohesin is required for holding sister chromatids together whereas condensin, together with topoisomerase II, has an important role in organizing (...) individual axes of sister chromatids prior to their segregation during anaphase. SMC and kleisin complexes also regulate the compaction and segregation of bacterial nucleoids. New research suggests that these ancient regulators of chromosome structure might function as topological devices that trap chromosomal DNA between 50 nm long coiled coils. BioEssays 25:1178–1191, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Cohesin establishes sister‐chromatid cohesion during S phase to ensure proper chromosome segregation in mitosis. It also facilitates postreplicative homologous recombination repair of DNA double‐strand breaks by promoting local pairing of damaged and intact sister chromatids. In G2 phase, cohesin that is not bound to chromatin is inactivated, but its reactivation can occur in response to DNA damage. Recent papers by Koshland's and Sjögren's groups describe the critical role of the known cohesin cofactor Eco1 (Ctf7) and ATR checkpoint kinase in (...) damage‐induced reactivation of cohesin, revealing an intricate mechanism that regulates sister‐chromatid pairing to maintain genome integrity.1,2 BioEssays 30:5–9, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Non‐coding centromeres, which dictate kinetochore formation for proper chromosome segregation, are extremely divergent in DNA sequences across species but are under active transcription carried out by RNA polymerase (RNAP) II. The RNAP II‐mediated centromeric transcription has been shown to facilitate the deposition of the centromere protein A (CENP‐A) to centromeres, establishing a conserved and critical role of centromeric transcription in centromere maintenance. Our recent work revealed another role of centromeric transcription in chromosome segregation: maintaining centromeric cohesion during mitosis. Interestingly, (...) this role appears to be fulfilled through ongoing centromeric transcription rather than centromeric transcripts. In addition, we found that centromeric transcription may not require some of the traditional transcription initiation factors, suggestive of “uniqueness” in its regulation. In this review, we discuss the novel role and regulation of centromeric transcription as well as the potential underlying mechanisms. (shrink)