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)

Two mechanisms are available for the repair of DNA double‐strand breaks (DSBs) in eukaryotic cells: homology directed repair (HDR) and non‐homologous end‐joining (NHEJ). While NHEJ is not restricted to a particular phase of the cell cycle, it is incapable of accurately repairing DBSs that have suffered a loss or gain of nucleotide sequence information. In contrast, HDR achieves accurate repair of such DSBs by use of a sister chromatid as a DNA template, but is restricted (...) to cell cycle phases (S/G2) when such templates are available. In this scheme, G1 cells appear to lack a mechanism for the accurate repair of certain DSBs, and an ability to use alternative templates would be highly advantageous. Considered here, therefore, is the possibility that RNA transcripts are used as templates for HDR. Potential mechanisms for transcript‐templated HDR, and ways in which it might be detected, are presented. BioEssays 28:78–83, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

MutL family proteins contain an N‐terminal ATPase domain (NTD), an unstructured interdomain linker, and a C‐terminal domain (CTD), which mediates constitutive dimerization between subunits and often contains an endonuclease active site. Most MutL homologs direct strand‐specific DNA mismatch repair by cleaving the error‐containing daughter DNA strand. The strand cleavage reaction is poorly understood; however, the structure of the endonuclease active site is consistent with a two‐ or three‐metal ion cleavage mechanism. A motif required for this endonuclease activity is present (...) in the unstructured linker of Mlh1 and is conserved in all eukaryotic Mlh1 proteins, except those from metamonads, which also lack the almost absolutely conserved Mlh1 C‐terminal phenylalanine‐glutamate‐arginine‐cysteine (FERC) sequence. We hypothesize that the cysteine in the FERC sequence is autoinhibitory, as it sequesters the active site. We further hypothesize that the evolutionary co‐occurrence of the conserved linker motif with the FERC sequence indicates a functional interaction, possibly by linker motif‐mediated displacement of the inhibitory cysteine. This role is consistent with available data for interactions between the linker motif with DNA and the CTDs in the vicinity of the active site. (shrink)

Recently discovered transcription‐independent features of p53 involve the choice of DNA damage repair pathway after PARylation, and p53's complex formation with phosphoinositide lipids, PI(4,5)P2. PARylation‐mediated rapid accumulation of p53 at DNA damage sites is linked to the recruitment of downstream repair factors and tumor suppression. This links p53's capability to sense damaged DNA in vitro and its relevant functions in cells. Further, PI(4,5)P2 rapidly accumulates at damage sites like p53 and complexes with p53, while it is required for (...) ATR recruitment. These findings help explain how p53 and PI(4,5)P2 maintain genome stability by directing DNA repair pathway choice. Additionally, there is a strong correlation between p53 sequence homology, genome mutation rates as well as lifespans across various mammalian species. Further investigation is required to better understand the connections between genome stability, tumor suppression, longevity and the transcriptional‐independent function of p53. (shrink)

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)‐based “active genetic” elements developed in 2015 bypassed the fundamental rules of traditional genetics. Inherited in a super‐Mendelian fashion, such selfish genetic entities offered a variety of potential applications including: gene‐drives to disseminate gene cassettes carrying desired traits throughout insect populations to control disease vectors or pest species, allelic drives biasing inheritance of preferred allelic variants, neutralizing genetic elements to delete and replace or to halt the spread of gene‐drives, split‐drives with the core constituent (...) Cas9 endonuclease and guide RNA (gRNA) components inserted at separate genomic locations to accelerate assembly of complex arrays of genetic traits or to gain genetic entry into novel organisms (vertebrates, plants, bacteria), and interhomolog based copying systems in somatic cells to develop tools for treating inherited or infectious diseases. Here, we summarize the substantial advances that have been made on all of these fronts and look forward to the next phase of this rapidly expanding and impactful field. (shrink)

Mammalian telomeres have evolved safeguards to prevent their recognition as DNA double‐stranded breaks by suppressing the activation of various DNA sensing and repair proteins. We have shown that the telomere‐binding proteins TRF2 and RAP1 cooperate to prevent telomeres from undergoing aberrant homology‐directed recombination by mediating t‐loop protection. Our recent findings also suggest that mammalian telomere‐binding proteins interact with the nuclear envelope to maintain chromosome stability. RAP1 interacts with nuclear lamins through KU70/KU80, and disruption of RAP1 and TRF2 (...) function result in nuclear envelope rupture, promoting telomere‐telomere recombination to form structures termed ultrabright telomeres. In this review, we discuss the importance of the interactions between shelterin components and the nuclear envelope to maintain telomere homeostasis and genome stability. (shrink)

It has become apparent that difficulties to replicate telomeres concern not only the very ends of eukaryotic chromosomes. The challenges already start when the replication fork enters the telomeric repeats. The obstacles encountered consist mainly of noncanonical nucleic acid structures that interfere with replication if not resolved. Replication stress at telomeres promotes the formation of so‐called fragile telomeres displaying an abnormal appearance in metaphase chromosomes though their exact molecular nature remains to be elucidated. A substantial number of factors is required (...) to counteract fragility. In this review we promote the hypothesis that telomere fragility is not caused directly by an initial insult during replication but it results as a secondary consequence of DNA repair of damaged replication forks by the homologous DNA recombination machinery. Incomplete DNA synthesis at repair sites or partial chromatin condensation may become apparent as telomere fragility. Fragility and DNA repair during telomere replication emerges as a common phenomenon which exacerbates in multiple disease conditions. (shrink)

The repair of chromosomal double‐strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSB repair is the RecA/Rad51‐mediated process to match sequences at the broken end to homologous donor sequences that can be used as a template to repair the lesion. Here, in reviewing research about DSB repair, I consider the many factors that appear to play important roles in the successful search for homology by several homologous recombination (...) mechanisms. (shrink)

The eukaryotic genome is packaged into a periodic nucleoprotein structure termed chromatin. The repeating unit of chromatin, the nucleosome, consists of DNA that is wound nearly two times around an octamer of histone proteins. To facilitate DNA‐directed processes in chromatin, it is often necessary to rearrange or to mobilize the nucleosomes. This remodeling of the nucleosomes is achieved by the action of chromatin‐remodeling complexes, which are a family of ATP‐dependent molecular machines. Chromatin‐remodeling factors share a related ATPase subunit and (...) participate in transcriptional regulation, DNA repair, homologous recombination and chromatin assembly. In this review, we provide an overview of chromatin‐remodeling enzymes and discuss two possible mechanisms by which these factors might act to reorganize nucleosome structure. BioEssays 25:1192–1200, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Homologous recombination (HR) is required to protect and restart stressed replication forks. Paradoxically, the Mrc1 branch of the S phase checkpoints, which is activated by replicative stress, prevents HR repair at breaks and arrested forks. Indeed, the mechanisms underlying HR can threaten genome integrity if not properly regulated. Thus, understanding how cells avoid genetic instability associated with replicative stress, a hallmark of cancer, is still a challenge. Here I discuss recent results that support a model by which HR responds (...) to replication stress through replicative and repair activities that operate at different stages of the cell cycle (S and G2, respectively) and in distinct subnuclear structures. Remarkably, the replication checkpoint appears to control this scenario by inhibiting the assembly of HR repair centers at stressed forks during S phase, thereby avoiding genetic instability. (shrink)

“Functional homology” appears regularly in different areas of biological research and yet it is apparently a contradiction in terms—homology concerns identity of structure regardless of form and function. I argue that despite this conceptual tension there is a legitimate conception of ‘homology of function’, which can be recovered by utilizing a distinction from pre-Darwinian physiology (use versus activity) to identify an appropriate meaning of ‘function’. This account is directly applicable to molecular developmental biology and shares a connection (...) to the theme of hierarchy in homology. I situate ‘homology of function’ within existing definitions and criteria for structural assessments of homology, and introduce a criterion of ‘organization’ for judging function homologues, which focuses on hierarchically interconnected interdependencies (similar to relative position and connection for skeletal elements in structural homology). This analysis of biological concepts has at least three broad philosophical consequences: (1) it provides the grounds for the study of behavior and psychological categories as homologues; (2) it demonstrates that philosophers who take selected effect function as primary effectively ignore large portions of comparative, structural, and experimental research, thereby misconstruing biological reasoning and knowledge; and, (3) it underwrites causal generalizations, which illuminates inferences made from model organisms in experimental biology. (shrink)

A fundamental aspect of biological systems is their spatial organization. In development, regeneration and repair, directional signals are necessary for the proper placement of the components of the organism. Likewise, pathogens that invade other organisms rely on directional signals to target vulnerable areas. It is widely understood that chemical gradients are important directional signals in living systems. Less well recognized are electrical fields, which can also provide directional information. Small, steady electrical fields can directly guide cell movement and growth (...) and can generate chemical gradients of charged macromolecules against the leveling action of diffusion. At the site of a lesion in an ion‐transporting epithelium, for example, a substantial electrical field is instantly generated and may extend over many cell diameters. There are numerous other situations in which relatively long‐range electrical fields have been shown to exist naturally. Recently, there has been substantial progress in identifying specific processes that are controlled, to some extent, by these endogenous electrical fields. This review highlights these recent data and discusses possible mechanisms by which the fields might affect biological processes. BioEssays 25:759–766, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This study examines the conditions under which apologies help to elicit forgiveness and restore trust following trust violations between leaders and followers. The intentionality and severity of violations are examined in a critical incident study and a laboratory study. The results support a model in which forgiveness mediates the relation of apology quality and trust. More importantly, the moderation–mediation model shows that apology quality influenced forgiveness and subsequent trust following violations that were moderate in severity–intentionality combination. The effect of apologizing (...) affects trust directly without forgiveness when the severity–intentionality combination held minor or extreme intensity. The results suggest a range in which apologies are effective and enrich understanding of the conditions under which trust can be recovered through an apology–forgiveness process in leader–follower relationships. The contribution of the study lies in elucidating that the combination of severity and intentionality of leaders’ trust violations has greater importance than either one separately. (shrink)

The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of “difficult to repair” lesions such as double‐strand breaks without a repair template and eroded telomeres in telomerase‐deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure‐forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus (...) to the NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC‐facilitated repair. (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)

In the last 10 years, several authors including Griffiths and Matthen have employed classificatory principles from biology to argue for a radical revision in the way that we individuate psychological traits. Arguing that the fundamental basis for classification of traits in biology is that of ‘homology’ (similarity due to common descent) rather than ‘analogy’, or ‘shared function’, and that psychological traits are a special case of biological traits, they maintain that psychological categories should be individuated primarily by relations of (...) homology rather than in terms of shared function. This poses a direct challenge to the dominant philosophical view of how to define psychological categories, viz., ‘functionalism’. Although the implications of this position extend to all psychological traits, the debate has centered around ‘emotion’ as an example of a psychological category ripe for reinterpretation within this new framework of classification. I address arguments by Griffiths that emotions should be divided into at least two distinct classes, basic emotions and higher cognitive emotions, and that these two classes require radically different theories to explain them. Griffiths argues that while basic emotions in humans are homologous to the corresponding states in other animals, higher cognitive emotions are dependent on mental capacities unique to humans, and are therefore not homologous to basic emotions. Using the example of shame, I argue that (a) many emotions that are commonly classified as being higher cognitive emotions actually correspond to certain basic emotions, and that (b) the “higher cognitive forms” of these emotions are best seen as being homologous to their basic forms. (shrink)

Many of the current comparisons of taxic phylogenetic and biological homology in the context of morphology focus on what are seen as categorical distinctions between the two concepts. The first, it is claimed, identifies historical patterns of conservation and variation relating taxa; the second provides a causal framework for the explanation of this conservation and variation. This leads to the conclusion that the two need not be placed in conflict and are in fact compatible, having non-competing epistemic purposes or (...) mapping the same extensions in the form of monophyletic groupings (see Roth, The biological basis of homology 1–26, 1988; Sluys, J Zool Syst Evol Res 34:145–152, 1996; Abouheif, Trends Ecol Evol 12:405–408, 1997; Brigandt, J Exp Zool 299:9–17, 2003, Biol Philos 22:709–725, 2007; Assis and Brigandt, Evol Biol 36:248–255, 2009). This article argues that moves in this direction miss the essential disagreement between these concepts as they have been developed in the context of the debate concerning the best concept for evolutionary investigation. We should rather see these concepts employing a common fundamental methodological approach to homology, but disagreeing about how to apply the methodology effectively. Both concepts employ class reasoning, which pursues homologies as units of generalization—more precisely, as sources of reliable and relevant group-bound information in the form of shared underlying causes. The dispute can be better understood by two poles that structure such reasoning: the need for a reliable basis for projections about the causal history of shared structures, and the desire to identify homologous characters with more informative and specific causal information relevant to generalizing about evolutionary processes. Judgments in favor of one or the other in turn have affected the scope or extension of these competing homology concepts. (shrink)

Comprehending the origin of marine invertebrate larvae remains a key domain of research for evolutionary biologists, including the repeated origin of direct developmental modes in echinoids. In order to address the latter question, we surveyed existing evidence on relationships of homology between the ectoderm territories of two closely related sea urchin species in the genus Heliocidaris that differ in their developmental mode. Additionally, we explored a recently articulated idea about homology called ‘organizational homology’ (Muller 2003. In: Muller (...) GB, Newman SA, editors. Origination of organismal form: beyond the gene in developmental and evolutionary biology. Cambridge, MA: A Bradford Book, The MIT Press. p 51–69. ) in the context of this specific empirical case study. Applying the perspective of organizational homology to our experimental system of congeneric echinoids has led us to a new hypothesis concerning the ectoderm evolution in these species. The extravestibular ectoderm of the direct developer Heliocidaris erythrogramma is a novel developmental territory that arose as a fusion of the oral and aboral ectoderm territories found in indirect developing echinoids such as Heliocidaris tuberculata. This hypothesis instantiates a theoretical principle concerning the origin of developmental modules, ‘integration’, which has been neglected because the opposite theoretical principle, ‘parcellation’, is more readily observable in events such as gene duplication and divergence (Wagner 1996. Am Zool 36:36–43). J. Exp. Zool. (Mol. Dev. Evol.) 306B:18– 34, 2006. (shrink)

This article turns to the theoretical and practical aspects of recent abolitionist praxis to illuminate an expanded notion of politics that is attentive to lived experience and concerns for self-preservation, on the one hand, and to state- and citizen-oriented forms of political action, on the other. The incorporation of healing justice practices and self-care within movement spaces, the mutual-aid of homecoming rituals for those bailed out of jail, the development of transformative justice processes, link what Stefano Harney and Fred Moten (...) call the fugitive sociality of these spaces as opposed to direct political action. Challenging an opposition between sociality and politics, I argue that abolitionist praxis recognizes how restorative activities and fugitive spaces are not opposed to politics but are rather important and necessary ways of stimulating and sustaining activism. By incorporating and making these practices central, I argue that contemporary abolitionist praxis challenges theorists, debating the questions of whether and how racial repair might be possible, to reconsider their notions of politics. Specifically, this repair praxis suggests the limits of both state-centered and insurgent accounts of politics, absent practices focused on survival, to “make ready” citizens and institutions for abolition democracy. (shrink)

A complex approach to Martin Buber’s oeuvre requires a consideration of both his dialogical and pre-dialogical writings. The latter include in some cases emphases that differ substantially from the emphases promulgated in Ich und Du. I will focus on three essays from the final stage of Buber’s pre-dialogical period which contain reflections on the fighting individual. The comparison with Ernst Jünger’s reflections on the same motif will show the intellectual proximity between the two authors and will help us understand how (...) Buber’s thought was positioned shortly before his dialogical turn. While after this turn Buber and Jünger could be easily seen as polar opposites, this is not the case when we juxtapose their early reflections on the fighting individual in World War I. There are striking similarities which I denote as a homology, as there is no evidence of influence in either direction. The presented analysis provides an insight into Buber’s controversial pre-dialogical positions as well as into the more general processing of the World War I experience in Germanophone philosophy. (shrink)

This thesis aims to develop a domain-independent system for repairing faulty Datalog-like theories by combining three existing techniques: abduction, belief revision, and conceptual change. Accordingly, the proposed system is named the ABC repair system. Given an observed assertion and a current theory, abduction adds axioms, which explain that observation by making the corresponding assertion derivable from the expanded theory. Belief revision incorporates a new piece of information which conflicts with the input theory by deleting old axioms. Conceptual change uses (...) the reformation algorithm for blocking unwanted proofs or unblocking wanted proofs. The former two techniques change an axiom as a whole, while reformation changes the language in which the theory is written. These three techniques are complementary. But they have not previously been combined into one system. We are working on aligning these three techniques in ABC, which is capable of repairing logical theories with better result than each individual technique alone. In addition, ABC extends abduction and belief revision to operate on preconditions: the former deletes preconditions from rules, and the latter adds preconditions to rules. Datalog is used as the underlying logic of theories in this thesis, but the proposed system has the potential to be adapted to theories in other logics.Abstract prepared by Xue Li by taking directly from the thesis.E-mail: [email protected]. (shrink)

There have been several recent attempts to think about psychological kinds as homologies. Nevertheless, there are serious epistemic challenges for individuating homologous psychological kinds, or cognitive homologies. Some of these challenges are revealed when we look at competing claims of cognitive homology. This paper considers two competing homology claims that compare human anger with putative aggression systems of nonhuman animals. The competition between these hypotheses has been difficult to resolve in part because of what I call the boundary (...) problem: boundaries between instances of psychological kinds (e.g., anger and fear) cannot be directly observed. Thus, there are distinctive difficulties for individuating psychological kinds across lineages. I draw four conclusions from this case study: First, recent evidence from the neuroscience of fear suggests that one of the proposed homologies involves a straightforward conflation of anger and fear. Second, this conflation arises because of the boundary problem. Third, there is an implicit constraint on the operational criteria that is easy to overlook in the psychological case. In this case, ignoring the constraint is part of the problem. Fourth, this is a clear case in which knowledge of homology cannot be accumulated piecemeal. Identifying homologs of human anger requires identifying homologs of fear. (shrink)

DNA topoisomerases are enzymes that can modify, and may regulate, the topological state of DNA through concerted breaking and rejoining of the DNA strands. They have been believed to be directly involved in DNA excision repair, and perhaps to be required for the control of repair as well. The vicissitudes of this hypothesis provide a noteworthy example of the dangers of interpreting cellular phenomena without genetic information and vice versa.

Unlike the most well‐characterized prokaryotic polymerase, E. Coli DNA pol I, none of the eukaryotic polymerases have their own 5′ to 3′ exonuclease domain for nick translation and Okazaki fragment processing. In eukaryotes, FEN‐1 is an endo‐and exonuclease that carries out this function independently of the polymerase molecules. Only seven nucleases have been cloned from multicellular eukaryotic cells. Among these, FEN‐1 is intriguing because it has complex structural preferences; specifically, it cleaves at branched DNA structures. The cloning of FEN‐1 permitted (...) establishment of the first eukaryotic nuclease family, predicting that S. cerevisiae RAD2 (S. pombe Rad13) and its mammalian homolog, XPG, would have similar structural specficity. The FEN‐1 nuclease family includes several similar enzymes encoded by bacteriophages. The crystal structures of two enzymes in the FEN‐1 nuclease family have been solved and they provide a structural basis for the interesting steric requirements of FEN‐1 substrates. Because of their unique structural specificities, FEN‐1 and its family members have important roles in DNA replication, repair and, potentially, recombination. Recently, FEN‐1 was found to specifically associate with PCNA, explaining some aspects of FEN‐1 function during DNA replication and potentially in DNA repair. (shrink)

Replication forks inevitably stall at damaged DNA in every cell cycle. The ability to overcome DNA lesions is an essential feature of the replication machinery. A variety of specialized polymerases have recently been discovered, which enable cells to replicate past various forms of damage by a process termed translesion synthesis. Alternatively, homologous recombination can be used to restart DNA replication across the lesion. Genetic and biochemical studies have shed light on the impact of these two post‐replication repair pathways in (...) bacteria and yeast. In vertebrates, however, a genetic approach to study post‐replication repair has been compromised because many of the genes involved appear to be essential for embryonic development. We have taken advantage of the chicken cell line DT40 to perform a genetic analysis of translesion synthesis and homologous recombination and to characterize genetic interactions between these two pathways in vertebrates. In this article, we aim to summarize our current understanding of post‐replication repair in DT40 in the perspective of bacterial, yeast and mammalian genetics. BioEssays 26:151–158, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Long DNA palindromes pose a threat to genome stability. This instability is primarily mediated by slippage on the lagging strand of the replication fork between short directly repeated sequences close to the ends of the palindrome. The role of the palindrome is likely to be the juxtaposition of the directly repeated sequences by intrastrand base‐pairing. This intra‐strand base‐pairing, if present on both strands, results in a cruciform structure. In bacteria, cruciform structures have proved difficult to detect in vivo, suggesting that (...) if they form, they are either not replicated or are destroyed. SbcCD, a recently discovered exonuclease of Escherichia coli, is responsible for preventing the replication of long palindromes. These observations lead to the proposal that cells may have evolved a post‐replicative mechanism for the elimination and/or repair of large DNA secondary structures. (shrink)

Replication protein A (RPA) is the main eukaryotic single‐stranded DNA (ssDNA) binding protein, having essential roles in all DNA metabolic reactions involving ssDNA. RPA binds ssDNA with high affinity, thereby preventing the formation of secondary structures and protecting ssDNA from the action of nucleases, and directly interacts with other DNA processing proteins. Here, we discuss recent results supporting the idea that one function of RPA is to prevent annealing between short repeats that can lead to chromosome rearrangements by microhomology‐mediated end (...) joining or the formation of hairpin structures that are substrates for structure‐selective nucleases. We suggest that replication fork catastrophe caused by depletion of RPA could result from cleavage of secondary structures by nucleases, and that failure to cleave hairpin structures formed at DNA ends could lead to gene amplification. These studies highlight the important role RPA plays in maintaining genome integrity. (shrink)

Several DNA-damage detection and repair mechanisms have evolved to repair double-strand breaks induced by mutagens. Later in evolutionary history, DNA single- and double-strand cuts made possible immune diversity by V(D)J recombination and recombination at meiosis. Such cuts are induced endogenously and are highly regulated and controlled. In meiosis, DNA cuts are essential for the initiation of homologous recombination, and for the formation of joint molecule and crossovers. Many proteins that function during somatic DNA-damage detection and repair are (...) also active during homologous recombination. However, their meiotic functions may be altered from their somatic roles through localization, posttranslational modifications and/or interactions with meiosis-specific proteins. Presumably, somatic repair functions and meiotic recombination diverged during evolution, resulting in adaptations specific to sexual reproduction. BioEssays 27:795–808, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

During the evolution of aerobic life, antioxidant defence systems developed that either directly prevent oxidative modifications of the cellular constituents or remove the modified components. An example of the latter is the proteasome, which removes cytosolic oxidised proteins. Recently, a novel mechanism of activation of the nuclear 20S proteasome was discovered: automodified poly‐(ADP‐ribose) polymerase‐1 (PARP‐1) activates the proteasome to facilitate selective degradation of oxidatively damaged histones. Since activation of the PARP‐1 itself is induced by DNA damage and is supposed to (...) play a role in DNA repair, these new results suggest a joint role of PARP‐1 in the removal of oxidised nucleoproteins and in DNA repair. We hypothesise that PARP‐1 could provide a co‐ordinative link between two nuclear antioxidant defence systems, whose concerted activation would produce a fast and efficient restoration of the native chromatin structure following oxidative stress. BioEssays 24:1060–1065, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

DNA junctions are by‐products of recombinational repair, during which a damaged DNA sequence, assisted by RecA filament, invades an intact homologous DNA to form a joint molecule. The junctions are three‐strand or four‐strand depending on how many single DNA strands participate in joint molecules. In E. coli, at least two independent pathways to remove the junctions are proposed to operate. One is via RuvAB‐promoted migration of four‐strand junctions with their subsequent resolution by RuvC. In vivo, RuvAB and RuvC enzymes (...) might work in a single complex, a resolvasome, to clean DNA from used RecA filaments and to resolve four‐strand junctions. An alternative pathway for junction removal could be via RecG‐promoted branch migration of three‐strand junctions, provided that an as yet uncharacterized endonuclease activity incises one of the strands in the joint molecules. (shrink)

The autosomal recessive genetic disorder, Nijmegen Breakage Syndrome, is characterised by an excessively high risk for the development of lymphatic tumours and an extreme sensitivity towards ionising radiation. The most likely explanation for these characteristics, a deficiency in the repair of DNA lesions, has been greatly substantiated by the recent cloning of the gene mutated in Nijmegen Breakage Syndrome patients and the analysis of its protein product, nibrin. The direct involvement of this protein in the processing of DNA double (...) strand breaks caused by ionising radiation and those also necessary for normal DNA metabolism can be correlated with many of the cellular and clinical aspects of the disease, including the cancer predisposition of patients and their heterozygous relatives. BioEssays 21:649–656, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The present study explores the discursive practice of the hospitality industry in addressing competence-based, benevolence-based, and integrity-based accusations of trust violation made by dissatisfied customers on TripAdvisor. Authentic negative online reviews written by dissatisfied customers and the corresponding responses by hotel management downloaded directly from TripAdvisor are analyzed qualitatively with Nvivo10. Results show that hotel management has the strongest preference for apology, followed by implicit denial and then explicit denial when dealing with the three different types of accusations of trust (...) violation. The findings will enhance our understanding of trust and its repair, and benefit hospitality practitioners responsible for handling online criticisms and complaints. (shrink)

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have adopted multiple (...) pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The multiple activities of the RecA protein in DNA metabolism have inspired over a decade of research in dozens of laboratories around the world. This effort has nevertheless failed to yield an understanding of the mechanism of several RecA protein‐mediated processes, the DNA strand exchange reactions prominent among them. The major factors impeding progress are the invalid constraints placed upon the problem by attempting to understand RecA protein‐mediated DNA strand exchange within the context of an inappropriate biological paradigm – namely, (...) homologous genetic recombination as a mechanism for generating genetic diversity. In this essay I summarize genetic and biochemical data demonstrating that RecA protein evolved as the central component of a recombinational DNA repair system, with the generation of genetic diversity being a sometimes useful byproduct, and review the major in vitro activities of RecA protein from a repair perspective. While models proposed for both recombination and recombinational repair often make use of DNA strand cleavage and transfer steps that appear to be quite similar, the molecular and thermodynamic requirements of the two processes are very different. The recombinational repair function provides a much more logical and informative framework for thinking about the biochemical properties of RecA and the strand exchange reactions it facilitates. (shrink)

Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard‐of‐care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting how specific (...) DNA repair proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease. (shrink)

Drawing on a corpus of eight task-based interactions involving a map task ), this article seeks to focus on how speakers orient to directional terms in an interactional context, and in so doing, to add to features that can be deemed to characterize this speech exchange system. Analysis of the data using conversation analysis showed that features of the talk were confirmation and clarification checks, which provided an opportunity to check understanding and the accuracy of the instruction leading to a (...) correction, acknowledgement or further information; modulated repair and mitigated criticism, resulting in the maintenance of an affiliative stance towards the other speaker; and avoidance of problems that viewpoints or directional terms might cause. Problems with the directional terms in this corpus confirm prior research that the confusion between east and west, and left and right are the terms that cause problems for speakers. (shrink)

Quartz & Sejnowski find flaws in standard theories of neural selection, which they propose to repair by introducing Lamarckian mechanisms for anatomical refinement that are analogous to directed mutation in evolution. The reversal of cause and effect that these mechanisms require is no more plausible in an explanation of cognition than it is in an explanation of evolution.

This paper examines how international law contributes to contemporary understandings of transitional justice with respect to reparations for victims of gross and systematic human rights abuses. The author surveys the jurisprudence of the Inter-American Court of Human Rights through 2003 to determine how the Court’s practice can be used to guide the formulation of reparatory policies during political transition. Recognizing that the direct application of Inter-American case law to situations of mass atrocity is not always viable in practice, the author (...) analyzes regional human rights jurisprudence, particularly that relating to compensation, to determine what role the Court’s rules can and cannot play as a reference for policymakers and societies faced with the challenge of designing a reparations program. He concludes that while landmark Court decisions like Velásquez Rodríguez provide general normative guidance, there are significant obstacles to extending to the transitional justice context many of the measures, amounts, and formulas relied upon by the Court in awarding compensation. The fairness of compensation outside the courtroom cannot be determined with reference to predetermined rules, but depends on the factual context in which the measures are adopted including the number of victims involved. A better source of comparative inspiration is found in the Court’s growing practice of adopting non-monetary reparations measures to deal with moral harm. (shrink)

The left must confront the politics of removing carbon from the atmosphere – a topic rapidly making its way to the top of the climate agenda. We here examine the technology of direct air capture, tracing its intellectual origins and laying bare the political economy of its current manifestations. We find a space crowded with ideology-laden metaphors, ample fossil-capital entanglements and bold visions for a new, ethereal frontier of capital accumulation. These diversions must be cut short if a technology with (...) the capacity to help repair at least some climate damage is to be of any use. Only socialising the means of removal will allow this to happen. (shrink)

Causal modeling methods such as path analysis, used in the social and natural sciences, are also highly relevant to philosophical problems of probabilistic causation and statistical explanation. We show how these methods can be effectively used (1) to improve and extend Salmon's S-R basis for statistical explanation, and (2) to repair Cartwright's resolution of Simpson's paradox, clarifying the relationship between statistical and causal claims.

RNA polymerase II is recruited to DNA double‐strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage‐induced long non‐coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA‐like molecules or degraded by different ribonucleases. They can also form double‐stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute (...) to the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR. (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 (...) class='Hi'>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)

New possibilities to modify function and direct repair in the central nervous system (CNS) have been established by the merger of gene transfer technology with neural transplantation. Rapid advances in viral‐mediated DNA‐delivery procedures permit the study of novel gene expression in neurons and glial cells. Foreign genes, transferred by a virus vector, can be used to generate new cell lines, identify transplanted cells, and express growth factors or enzymes for neurotransmitter synthesis. In addition to CNS cell types, non‐neural cells (...) are also being studied with transgene technology in the nervous system. Functional effects have been obtained with grafts of genetically modified cells in animal models of several nervous system disorders, and the recent results set the stage for potential application of these techniques to human CNS gene therapy. (shrink)

Homologous recombination (HR) is essential for the accurate repair of DNA double‐strand breaks and damaged replication forks. However, inappropriate or aberrant HR can also result in genome rearrangements. The maintenance of cell viability is, therefore, a careful balancing act between the benefits of HR (the error‐free repair of DNA strand breaks) and the potential detrimental outcomes of HR (chromosomal rearrangements). Two papers have recently provided a mechanistic insight into how HR may be tempered by RecQ helicases to prevent (...) genome instability and diseases that are a consequence of this, such as cancer.1,2 BioEssays 30:291–295, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cells mitigate the detrimental consequences of DNA damage on genome stability by attempting high fidelity repair. Homologous recombination templates DNA double‐strand break (DSB) repair on an identical or near identical donor sequence in a process that can in principle access the entire genome. Other physiological processes, such as homolog recognition and pairing during meiosis, also harness the HR machinery using programmed DSBs to physically link homologs and generate crossovers. A consequence of the homology search process by a (...) long nucleoprotein filament is the formation of multi‐invasions (MI), a joint molecule in which the damaged ssDNA has invaded more than one donor molecule. Processing of MI joint molecules can compromise the integrity of both donor sites and lead to their rearrangement. Here, two mechanisms for the generation of rearrangements as a pathological consequence of MI processing are detailed and the potential relevance for non‐allelic homologous recombination discussed. Finally, it is proposed that MI‐induced crossover formation may be a feature of physiological recombination. (shrink)

Recent research indicates that interpersonal communication is noisy, and that people exhibit considerable insensitivity to problems in communication. Using a dyadic referential communication task, the goal of which is accurate information transfer, this study examined the extent to which interlocutors are sensitive to problems in communication and use other‐initiated repairs (OIRs) to address them. Participants were randomly assigned to dyads (N = 88 participants, or 44 dyads) and tried to communicate a series of recurring abstract geometric shapes to a partner (...) across a text–chat interface. Participants alternated between directing (describing shapes) and matching (interpreting shape descriptions) roles across 72 trials of the task. Replicating prior research, over repeated social interactions communication success improved and the shape descriptions became increasingly efficient. In addition, confidence in having successfully communicated the different shapes increased over trials. Importantly, matchers were less confident on trials in which communication was unsuccessful, communication success was lower on trials that contained an OIR compared to those that did not contain an OIR, and OIR trials were associated with lower Director Confidence. This pattern of results demonstrates that (a) interlocutors exhibit (a degree of) sensitivity to problems in communication, (b) they appropriately use OIRs to address problems in communication, and (c) OIRs signal problems in communication. (shrink)

Clamp loaders are pentameric AAA+ assemblies that use ATP to open and close circular DNA sliding clamps around DNA. Clamp loaders show homology in all organisms, from bacteria to human. The eukaryotic PCNA clamp is loaded onto 3′ primed DNA by the replication factor C (RFC) hetero‐pentameric clamp loader. Eukaryotes also have three alternative RFC‐like clamp loaders (RLCs) in which the Rfc1 subunit is substituted by another protein. One of these is the yeast Rad24‐RFC (Rad17‐RFC in human) that loads (...) a 9‐1‐1 heterotrimer clamp onto a recessed 5′ end of DNA. Recent structural studies of Rad24‐RFC have discovered an unexpected 5′ DNA binding site on the outside of the clamp loader and reveal how a 5′ end can be utilized for loading the 9‐1‐1 clamp onto DNA. In light of these results, new studies reveal that RFC also contains a 5′ DNA binding site, which functions in gap repair. These studies also reveal many new features of clamp loaders. As reviewed herein, these recent studies together have transformed our view of the clamp loader mechanism. (shrink)

-/- Feminist philosophers Barrett Emerick and Audrey Yap bring theoretical arguments about personhood and moral repair into conversation with the work of activists and the experiences of incarcerated people to make the case that prisons ought to be abolished. They argue that contemporary carceral systems in the United States and Canada fail to treat people as genuine moral agents in ways that also fail victims and their larger communities. Such carceral systems are a form of what Emerick and Yap (...) call “institutionalized moral abandonment”. Instead, they argue that we should create communities of moral solidarity which open up space for wrongdoers to make up for their wrongs. -/- As part of this argument, the book directly addresses one of the paradigm cases of wrongdoing often used to justify carceral systems: rape. Carceral systems that treat perpetrators of sexual violence as irredeemable monsters both obscure the reality of sexual violence and are harmful to everyone involved. -/- As an alternative to carceral systems, Emerick and Yap argue for an orientation towards justice that is grounded in moral repair. This incorporates elements of restorative justice, mutual aid, and harm reduction. Instead of advocating for one specific and universal approach, the authors argue for multigenerational collective action that aims to build resilient communities that support the wellbeing of everyone. (shrink)