Late Origins Research Articles

The origin of phagocytosis in Earth history.

Phagocytosis, or 'cell eating', is a eukaryote-specific process where particulate matter is engulfed via invaginations of the plasma membrane. The origin of phagocytosis has been central to discussions on eukaryogenesis for decades-, where it is argued as being either a prerequisite for, or consequence of, the acquisition of the ancestral mitochondrion. Recently, genomic and cytological evidence has increasingly supported the view that the pre-mitochondrial host cell-a bona fide archaeon branching within the 'Asgard' archaea-was incapable of phagocytosis and used alternative mechanisms to incorporate the alphaproteobacterial ancestor of mitochondria. Indeed, the diversity and variability of proteins associated with phagosomes across the eukaryotic tree suggest that phagocytosis, as seen in a variety of extant eukaryotes, may have evolved independently several times within the eukaryotic crown-group. Since phagocytosis is critical to the functioning of modern marine food webs (without it, there would be no microbial loop or animal life), multiple late origins of phagocytosis could help explain why many of the ecological and evolutionary innovations of the Neoproterozoic Era (e.g. the advent of eukaryotic biomineralization, the 'Rise of Algae' and the origin of animals) happened when they did.

Nucleosides Rescue Replication-Mediated Genome Instability of Human Pluripotent Stem Cells.

SummaryHuman pluripotent stem cells (PSCs) are subject to the appearance of recurrent genetic variants on prolonged culture. We have now found that, compared with isogenic differentiated cells, PSCs exhibit evidence of considerably more DNA damage during the S phase of the cell cycle, apparently as a consequence of DNA replication stress marked by slower progression of DNA replication, activation of latent origins of replication, and collapse of replication forks. As in many cancers, which, like PSCs, exhibit a shortened G1 phase and DNA replication stress, the resulting DNA damage may underlie the higher incidence of abnormal and abortive mitoses in PSCs, resulting in chromosomal non-dysjunction or cell death. However, we have found that the extent of DNA replication stress, DNA damage, and consequent aberrant mitoses can be substantially reduced by culturing PSCs in the presence of exogenous nucleosides, resulting in improved survival, clonogenicity, and population growth.

DNMT3A with Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks

Mutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent in de novoacute myeloid leukemia (AML) and are associated with poor prognosis. Although studies demonstrated survival benefit of induction chemotherapy dose intensification, outcomes remain unsatisfactory in most patients due to advanced age, comorbidities, and hence inability to tolerate treatment. Clinical trials of low-intensity regimens combining cytarabine and cladribine, nucleoside analog chain terminators that stall DNA replication, appear to be safe and effective, and tend to particularly benefit patients with DNMT3Amutations. Consistently, we observe increased sensitivity to cytarabine, fludarabine, and cladribine in multiple cellular systems harboring mutant DNMT3Ain vitro (Figure 1A, B). Differential sensitivity to cytarabine was confirmed in normal and leukemic primary bone marrow cells derived from mice with and without Dnmt3a mutations ex vivo (Figure 1C). Dynamic chromatin organization plays a pivotal role in DNA-associated cellular processes including DNA replication and damage repair. We previously found altered chromatin remodeling in cells expressing mutant DNMT3A after genotoxic stress. Gene expression studies by us and others demonstrated negative enrichment of cell cycle related signatures including G2/M checkpoint adaptation, in cells with DNMT3A mutations. These signatures are implicated in DNA damage response and replication fork integrity and suggest sensitivity to replication stress. To investigate the mechanism of differential sensitivity to cytarabine-induced DNA damage, we overexpressed wildtype (WT) or R882 mutant (MUT) forms of DNMT3A in U2OS cells, a well-established model for DNA damage studies. Analysis of the DNA damage signaling proficiency in response to cytarabine revealed persistent intra-S phase checkpoint activation (phospho-CHK1), accompanied by accumulation of DNA damage visualized by γH2A.X foci and by Comet assay in the DNMT3A(mut) overexpression cells (Figure 1D). This damage was only partially resolved after drug had been removed and cells were allowed to repair the DNA (Figure 1E), and was carried through mitosis, resulting in increased rate of micronucleation.At the same time, DNMT3A mutant cells remained proficient in initiating homology-directed repair (HDR) and non-homologous end joining (NHEJ) pathways, evidenced by RAD51 and 53BP-1 foci formation, respectively. These data demonstrate enhanced sensitivity to cytarabine in cells expressing mutant DNMT3A is due to increased susceptibility to DNA damage during replication, rather than defects in double-strand DNA break repair. In support of this, cells with mutant DNMT3Awere characterized by accentuated replication stress as evidenced by high levels of phospho-RPA, which persisted after drug wash-out (Figure 1F). Consistently, DNMT3A-mutant cells treated with cytarabine were characterized by a higher number and a larger area of PCNA foci. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine wash-out demonstrated that while the overall kinetics of replication restart remained unchanged, cells with DNMT3A(mut) showed higher rate of fork collapse and increased reliance on latent replication origins (Figure 1G). Gene expression profiling by RNA-seq identified dysregulation of pathways associated with cell cycle progression, specifically G1/S phase transition, DNA replication, DNA integrity checkpoint, and chromatin. Our studies show cells with DNMT3A mutations have a defect in recovery from replication fork arrest and subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during DNA replication and suggest that cytarabine-induced replication fork stalling may further synergize with other agents aimed at DNA damage and replication. Figure 1 Disclosures No relevant conflicts of interest to declare.

Telomere DNA length-dependent regulation of DNA replication timing at internal late replication origins

DNA replication is initiated at replication origins on chromosomes at their scheduled time during S phase of the cell cycle. Replication timing control is highly conserved among eukaryotes but the underlying mechanisms are not fully understood. Recent studies have revealed that some telomere-binding proteins regulate replication timing at late-replicating origins throughout the genome. To investigate the molecular basis of this process, we analyzed the effects of excessive elongation of telomere DNA on replication timing by deleting telomere-associated shelterin proteins in Schizosaccharomyces pombe. We found that rap1∆ and poz1∆ cells showed abnormally accelerated replication at internal late origins but not at subtelomere regions. These defects were suppressed by removal of telomere DNA and by deletion of the telomere-binding protein Taz1. Furthermore, Sds21—a counter protein phosphatase against Dbf4-dependent kinase (DDK)—accumulated at elongated telomeres in a Taz1-dependent manner but was depleted at internal late origins, indicating that highly elongated telomeres sequester Sds21 at telomeres and perturb replication timing at internal regions. These results demonstrate that telomere DNA length is an important determinant of replication timing at internal regions of chromosomes in eukaryotes.

Physical characterization of the hair of Mexican women.

Hairs collected from 257 Mexican women, residing in Mexico City, were characterized by instrumental measurements for comparison to more-commonly reported Caucasian, Asian and African hairs. Subjects were subdivided into five age groups and their hairs were characterized by fibre dimension, shape and tensile strength. Results show that Mexican hair appears to be intermediate of Asian and Caucasian hair in diameter and cross-sectional ellipticity. Such findings seem in line with the early and late ethnic origins of Mexican people. Results also illustrate and confirm the large intra- and inter-individual variability within any single hair property. Unexpectedly high levels of hair tensile damage were sometimes encountered.

On the Interplay of the DNA Replication Program and the Intra-S Phase Checkpoint Pathway.

DNA replication in eukaryotes is achieved by the activation of multiple replication origins which needs to be precisely coordinated in space and time. This spatio-temporal replication program is regulated by many factors to maintain genome stability, which is frequently threatened through stresses of exogenous or endogenous origin. Intra-S phase checkpoints monitor the integrity of DNA synthesis and are activated when replication forks are stalled. Their activation leads to the stabilization of forks, to the delay of the replication program by the inhibition of late firing origins, and the delay of G2/M phase entry. In some cell cycles during early development these mechanisms are less efficient in order to allow rapid cell divisions. In this article, we will review our current knowledge of how the intra-S phase checkpoint regulates the replication program in budding yeast and metazoan models, including early embryos with rapid S phases. We sum up current models on how the checkpoint can inhibit origin firing in some genomic regions, but allow dormant origin activation in other regions. Finally, we discuss how numerical and theoretical models can be used to connect the multiple different actors into a global process and to extract general rules.

The development of the Church of St Mary at Ephesos from late antiquity to the Dark Ages

AbstractThe Church of St Mary is one of the most significant monuments of Ephesos, but also one of the most enigmatic. Its repeated modifications prior to its destruction created an amalgam of different phases that have proven difficult to decipher within the present remains. Written records and inscriptions suggest that this church was the venue of the riotous Ecumenical Council of AD 431, but the identification of the phase of the building that corresponds to this event is controversial. And, although the remains make it clear that at some point the church was transformed into a domed basilica, the latter’s form and date have not been established with certainty. The present article tries to fill these lacunae through a new survey of the remains of the church and a re-examination of the evidence from the archaeological excavations of the 20th century. This new investigation of wall structures and design patterns within the remains leads to new interpretations of the evidence, and sheds further light on the history of the Church of St Mary from its late antique origins to the Dark Ages.

Shelterin promotes tethering of late replication origins to telomeres for replication‐timing control

DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast Schizosaccharomyces pombe, the telomere-binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere-like sequence near the origins. Here, we showed using a lacO/LacI-GFP system that Taz1-dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase. The peripheral localization that depended on the nuclear membrane protein Bqt4 was not necessary for telomeric association and replication-timing control of the replication origins. Interestingly, the shelterin components Rap1 and Poz1 were required for replication-timing control and telomeric association of Taz1-dependent late origins, and this requirement was bypassed by a minishelterin Tpz1-Taz1 fusion protein. Our results suggest that Taz1 suppresses replication initiation through shelterin-mediated telomeric association of the origins at the onset of S phase.

Reconstructing the origins and the biogeography of species’ genomes in the highly reticulate allopolyploid-rich model grass genus Brachypodium using minimum evolution, coalescence and maximum likelihood approaches

The identification of homeologous genomes and the biogeographical analyses of highly reticulate allopolyploid-rich groups face the challenge of incorrectly inferring the genomic origins and the biogeographical patterns of the polyploids from unreliable strictly bifurcating trees. Here we reconstruct a plausible evolutionary scenario of the diverging and merging genomes inherited by the diploid and allopolyploid species and cytotypes of the model grass genus Brachypodium. We have identified the ancestral Brachypodium genomes and inferred the paleogeographical ranges for potential hybridization events that originated its allopolyploid taxa. We also constructed a comprehensive phylogeny of Brachypodium from five nuclear and plastid genes using Species Tree Minimum Evolution allele grafting and Species Network analysis. The divergence ages of the lineages were estimated from a consensus maximum clade credibility tree using fossil calibrations, whereas ages of origin of the diploid and allopolyploid species were inferred from coalescence Bayesian methods. The biogeographical events of the genomes were reconstructed using a stratified Dispersal-Extinction-Colonization model with three temporal windows. Our combined Minimum Evolution-coalescence-Bayesian approach allowed us to infer the origins and the identities of the homeologous genomes of the Brachypodium allopolyploids, matching the expected ploidy levels of the hybrids. To date, the current extant progenitor genomes (species) are only known for B. hybridum. Putative ancestral homeologous genome have been inherited by B. mexicanum, ancestral and recent genomes by B. boissieri, and only recently evolved genomes by B. retusum and the core perennial clade allopolyploids (B. phoenicoides, B. pinnatum 4x, B. rupestre 4x). We dissected the complex spatio-temporal evolution of ancestral and recent genomes and have detected successive splitting, dispersal and merging events for dysploid homeologous genomes in diverse geographical scenarios that have led to the current extant taxa. Our data support Mid-Miocene splits of the Holarctic ancestral genomes that preceded the Late Miocene origins of Brachypodium ancestors of the modern diploid species. Successive divergences of the annual B. stacei and B. distachyon diploid genomes were implied to have occurred in the Mediterranean region during the Late Miocene-Pliocene. By contrast, a profusion of splits, range expansions and different genome mergings were inferred for the perennial diploid genomes in the Mediterranean and Eurasian regions, with sporadic colonizations and further mergings in other continents during the Quaternary. A reliable biogeographical scenario was obtained for the Brachypodium genomes and allopolyploids where homeologous genomes split from their respective diploid counterpart lineages in the same ancestral areas, showing similar or distinct dispersals. By contrast, the allopolyploid taxa remained in the same ancestral ranges after hybridization and genome doubling events. Our approach should have utility in deciphering the genomic composition and the historical biogeography of other allopolyploid-rich organismal groups, which are predominant in eukaryotes.

Cross Bones Graveyard: Excavating the Prostitute in Neo-Victorian Popular Culture

Cross Bones graveyard, an unconsecrated burial site in Southwark, London, was rediscovered in 1989 when Transport for London sought to extend the Jubilee Line, part of the Underground railway network. Subsequent archaeological investigations estimated that about 15,000 bodies were interred at the site, which covers only about 2000 square yards. From its late medieval origins until 1853, when it closed due to its being ‘overcharged with dead’, Cross Bones was synonymous with poverty and disease.1 Historically, Southwark was also the home to the licentious, the criminal, and those escaping justice, and has a unique legacy and history which informs how Cross Bones has been received and interpreted. Under the jurisdiction of the Bishop of Winchester, medieval Southwark was outside the conventional law of the King and the City, and as such, entertainments such as bear-baiting, playhouses (including Shakespeare’s Globe), and prostitution became commonplace, and effectively licensed by the church.2 By the Victorian period, Southwark was marked by low-standard housing: ‘each house is occupied by several families – indeed, the houses are crammed full of the poorest and most wretched of our inhabitants. The houses being so old, and built of wood, are literally alive with vermin’.3 Museum of London Archaeology’s excavation of the graveyard bears witness to these conditions: the pauper coffins and the fact that bodies were stacked nine or ten deep, point to the poverty of the people who lived nearby. Cross Bones is also frequently identified as a prostitute’s or ‘single woman’s’ burial ground, licensed as such by the Bishop of Winchester, but where such women were denied formal religious rites in death.

Unexpected roles of a shugoshin protein at subtelomeres

A chromosome is composed of structurally and functionally distinct domains. Telomeres, which are located at the ends of linear chromosomes, play crucial roles in genome stability. Although substantial knowledge of telomeres has been accumulated, the regulation and function of subtelomeres, which are the domains adjacent to telomeres, remain largely unknown. In this review, I describe recent discoveries about the multiple roles of a shugoshin family protein, Sgo2, which is localized at centromeres in mitosis and contributes to precise chromosome segregation, in defining chromatin structure and functions of the subtelomeres in fission yeast. Sgo2 becomes enriched at the subtelomeres, particularly during G2 phase, and is essential for the formation of a highly condensed subtelomeric chromatin body called the knob. Furthermore, Sgo2 maintains the expression levels of subtelomeric genes and the timing of DNA replication at subtelomeric late origins.

'AND' logic gates at work: Crystal structure of Rad53 bound to Dbf4 and Cdc7.

Forkhead-associated (FHA) domains are phosphopeptide recognition modules found in many signaling proteins. The Saccharomyces cerevisiae protein kinase Rad53 is a key regulator of the DNA damage checkpoint and uses its two FHA domains to interact with multiple binding partners during the checkpoint response. One of these binding partners is the Dbf4-dependent kinase (DDK), a heterodimer composed of the Cdc7 kinase and its regulatory subunit Dbf4. Binding of Rad53 to DDK, through its N-terminal FHA (FHA1) domain, ultimately inhibits DDK kinase activity, thereby preventing firing of late origins. We have previously found that the FHA1 domain of Rad53 binds simultaneously to Dbf4 and a phosphoepitope, suggesting that this domain functions as an ‘AND’ logic gate. Here, we present the crystal structures of the FHA1 domain of Rad53 bound to Dbf4, in the presence and absence of a Cdc7 phosphorylated peptide. Our results reveal how the FHA1 uses a canonical binding interface to recognize the Cdc7 phosphopeptide and a non-canonical interface to bind Dbf4. Based on these data we propose a mechanism to explain how Rad53 enhances the specificity of FHA1-mediated transient interactions.

Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells

To prevent rereplication of genomic segments, the eukaryotic cell cycle is divided into two nonoverlapping phases. During late mitosis and G1 replication origins are "licensed" by loading MCM2-7 double hexamers and during S phase licensed replication origins activate to initiate bidirectional replication forks. Replication forks can stall irreversibly, and if two converging forks stall with no intervening licensed origin-a "double fork stall" (DFS)-replication cannot be completed by conventional means. We previously showed how the distribution of replication origins in yeasts promotes complete genome replication even in the presence of irreversible fork stalling. This analysis predicts that DFSs are rare in yeasts but highly likely in large mammalian genomes. Here we show that complementary strand synthesis in early mitosis, ultrafine anaphase bridges, and G1-specific p53-binding protein 1 (53BP1) nuclear bodies provide a mechanism for resolving unreplicated DNA at DFSs in human cells. When origin number was experimentally altered, the number of these structures closely agreed with theoretical predictions of DFSs. The 53BP1 is preferentially bound to larger replicons, where the probability of DFSs is higher. Loss of 53BP1 caused hypersensitivity to licensing inhibition when replication origins were removed. These results provide a striking convergence of experimental and theoretical evidence that unreplicated DNA can pass through mitosis for resolution in the following cell cycle.

Ringiculid bubble snails recovered as the sister group to sea slugs (Nudipleura).

Euthyneuran gastropods represent one of the most diverse lineages in Mollusca (with over 30,000 species), play significant ecological roles in aquatic and terrestrial environments and affect many aspects of human life. However, our understanding of their evolutionary relationships remains incomplete due to missing data for key phylogenetic lineages. The present study integrates such a neglected, ancient snail family Ringiculidae into a molecular systematics of Euthyneura for the first time, and is supplemented by the first microanatomical data. Surprisingly, both molecular and morphological features present compelling evidence for the common ancestry of ringiculid snails with the highly dissimilar Nudipleura—the most species-rich and well-known taxon of sea slugs (nudibranchs and pleurobranchoids). A new taxon name Ringipleura is proposed here for these long-lost sisters, as one of three major euthyneuran clades with late Palaeozoic origins, along with Acteonacea (Acteonoidea + Rissoelloidea) and Tectipleura (Euopisthobranchia + Panpulmonata). The early Euthyneura are suggested to be at least temporary burrowers with a characteristic ‘bubble’ shell, hypertrophied foot and headshield as exemplified by many extant subtaxa with an infaunal mode of life, while the expansion of the mantle might have triggered the explosive Mesozoic radiation of the clade into diverse ecological niches.

Ancestral range reconstruction of Galliformes: the effects of topology and taxon sampling

AbstractAimWe examined divergence times and biogeography of the avian order Galliformes (which, despite a nearly world‐wide distribution, includes many weak fliers), to test whether current distributions reflect vicariance or long‐distance dispersal. We also tested the impact of taxon sampling and tree topology on our estimates of historical biogeography.LocationWorld‐wide.MethodsWe generated timetrees for all major galliform lineages using several fossil calibrations and a combination of mitochondrial and nuclear data. We compared divergence times and reconstructed ancestral ranges using this timetree and the galliforms from a recent synthetic tree for all birds. Thus, we explored the sensitivity of our conclusions to differences in topology and taxon sampling.ResultsThe results suggest late Cretaceous origins for Megapodiidae and possibly for Cracidae, the earliest diverging families. The other families diversified in the Eocene after the break‐up of Gondwana, contrary to previous suggestions. Both topology and taxon sampling affected the ancestral area estimates, although many nodes were consistent among the approaches.Main conclusionsDivergences of Numididae, Odontophoridae and Phasianidae occurred in Africa, with subsequent dispersal to other continents. Reconstructed ranges for ancestors of the earliest diverging families, Megapodiidae and Cracidae, are less conclusive, but may have involved a South American origin, then dispersal to other continents. Thus, long‐distance dispersal is likely to have been important in galliforms, possibly reflecting more vagile ancestors and repeated range expansions and contractions. There appears to be a trade‐off between the use of trees with rich taxon sampling but limited data, where key taxa can be misplaced, and more robust trees with missing taxa. When biogeographically important taxa are included, complete taxon sampling does not appear necessary for accurate ancestral area reconstruction. Robust trees that include taxa targeted based on their distribution may be the best way to improve our understanding of historical biogeography.

Taz1-Shelterin Promotes Facultative Heterochromatin Assembly at Chromosome-Internal Sites Containing Late Replication Origins

Facultative heterochromatin regulates gene expression, but its assembly is poorly understood. Previously, we identified facultative heterochromatin islands in the fission yeast genome and found that RNA elimination machinery promotes island assembly at meiotic genes. Here, we report that Taz1, a component of the telomere protection complex Shelterin, is required to assemble heterochromatin islands at regions corresponding to late replication origins that are sites of double-strand break formation during meiosis. The loss of Taz1 or other Shelterin subunits, including Ccq1 that interacts with Clr4/Suv39h, abolishes heterochromatin at late origins and causes derepression of associated genes. Moreover, the late-origin regulator Rif1 affects heterochromatin at Taz1-dependent islands and subtelomeric regions. We explore the connection between facultative heterochromatin and replication control and show that heterochromatin machinery affects replication timing. These analyses reveal the role of Shelterin in facultative heterochromatin assembly at late origins, which has important implications for genome stability and gene regulation.

Spatially coordinated replication and minimization of expression noise constrain three-dimensional organization of yeast genome.

Despite recent advances, the underlying functional constraints that shape the three-dimensional organization of eukaryotic genome are not entirely clear. Through comprehensive multivariate analyses of genome-wide datasets, we show that cis and trans interactions in yeast genome have significantly distinct functional associations. In particular, (i) the trans interactions are constrained by coordinated replication and co-varying mutation rates of early replicating domains through interactions among early origins, while cis interactions are constrained by coordination of late replication through interactions among late origins; (ii) cis and trans interactions exhibit differential preference for nucleosome occupancy; (iii) cis interactions are also constrained by the essentiality and co-fitness of interacting genes. Essential gene clusters associate with high average interaction frequency, relatively short-range interactions of low variance, and exhibit less fluctuations in chromatin conformation, marking a physically restrained state of engaged loci that, we suggest, is important to mitigate the epigenetic errors by restricting the spatial mobility of loci. Indeed, the genes with lower expression noise associate with relatively short-range interactions of lower variance and exhibit relatively higher average interaction frequency, a property that is conserved across Escherichia coli, yeast, and mESCs. Altogether, our observations highlight the coordination of replication and the minimization of expression noise, not necessarily co-expression of genes, as potent evolutionary constraints shaping the spatial organization of yeast genome.

Shugoshin forms a specialized chromatin domain at subtelomeres that regulates transcription and replication timing.

A chromosome is composed of structurally and functionally distinct domains. However, the molecular mechanisms underlying the formation of chromatin structure and the function of subtelomeres, the telomere-adjacent regions, remain obscure. Here we report the roles of the conserved centromeric protein Shugoshin 2 (Sgo2) in defining chromatin structure and functions of the subtelomeres in the fission yeast Schizosaccharomyces pombe. We show that Sgo2 localizes at the subtelomeres preferentially during G2 phase and is essential for the formation of a highly condensed subtelomeric chromatin body ‘knob'. Furthermore, the absence of Sgo2 leads to the derepression of the subtelomeric genes and premature DNA replication at the subtelomeric late origins. Thus, the subtelomeric specialized chromatin domain organized by Sgo2 represses both transcription and replication to ensure proper gene expression and replication timing.

Concerted activities of Mcm4, Sld3, and Dbf4 in control of origin activation and DNA replication fork progression.

Eukaryotic chromosomes initiate DNA synthesis from multiple replication origins in a temporally specific manner during S phase. The replicative helicase Mcm2-7 functions in both initiation and fork progression and thus is an important target of regulation. Mcm4, a helicase subunit, possesses an unstructured regulatory domain that mediates control from multiple kinase signaling pathways, including the Dbf4-dependent Cdc7 kinase (DDK). Following replication stress in S phase, Dbf4 and Sld3, an initiation factor and essential target of Cyclin-Dependent Kinase (CDK), are targets of the checkpoint kinase Rad53 for inhibition of initiation from origins that have yet to be activated, so-called late origins. Here, whole-genome DNA replication profile analysis is used to access under various conditions the effect of mutations that alter the Mcm4 regulatory domain and the Rad53 targets, Sld3 and Dbf4. Late origin firing occurs under genotoxic stress when the controls on Mcm4, Sld3, and Dbf4 are simultaneously eliminated. The regulatory domain of Mcm4 plays an important role in the timing of late origin firing, both in an unperturbed S phase and in dNTP limitation. Furthermore, checkpoint control of Sld3 impacts fork progression under replication stress. This effect is parallel to the role of the Mcm4 regulatory domain in monitoring fork progression. Hypomorph mutations in sld3 are suppressed by a mcm4 regulatory domain mutation. Thus, in response to cellular conditions, the functions executed by Sld3, Dbf4, and the regulatory domain of Mcm4 intersect to control origin firing and replication fork progression, thereby ensuring genome stability.

Children’s Literature and the Avant-Garde ed. by Elina Druker and Bettina Kümmerling-Meibauer

Reviewed by: Children’s Literature and the Avant-Garde ed. by Elina Druker and Bettina Kümmerling-Meibauer Carl F. Miller (bio) Children’s Literature and the Avant-Garde. Edited by Elina Druker and Bettina Kümmerling-Meibauer. Amsterdam: John Benjamins Publishing Company, 2015. Stemming from a 2012 international conference, this book offers a diverse study of the avant-garde in children’s literature, tackling a consideration that has often been suggested but rarely addressed with such intellectual rigor. Elina Druker and Bettina Kümmerling-Meibauer have assembled a collection that is interested not only in validating the study of the avant-garde within children’s literature, but also in using this relationship as validation for the study of children’s literature in general. Consequently, this text has applications that reach far beyond the field of children’s literature, and should be of interest to scholars and students of comparative literature, modern art, and literary periodization, among many other practical possibilities. The editors’ introduction first attempts to formulate a working concept of the avant-garde via historical overview, from its late nineteenthcentury origins to its association with a number of art movements of the early to mid-twentieth century, including expressionism, surrealism, and—both most especially and problematically—modernism. Much as the avant-garde is both culturally contingent and historically disparate, “avantgarde ideas about children’s literature often reflect a general desire to break free from aesthetic boundaries and labels” (5). The scholars contributing to this volume have uncovered a great many previously unseen materials that serve as fascinating precursors to some of the more recognizable contemporary children’s texts, in the process highlighting the mutual impact between the avant-garde and children’s literature in Europe and North America. Part 1, “Vanguard tendencies since the beginning of the twentieth century,” considers the early interplay of children’s culture and avant-garde development with chapters on John Ruskin (Marilynn S. Olson), Einar Nerman (Druker), Sándor Bortnyik (Samuel D. Albert), and the lost legacy of the early avant-garde British children’s book (Kimberley Reynolds). Olson’s assessment of Ruskin as an early champion of the avant-garde for children presents a logical lead-off to the book, as its effective background of children’s literature and art experiments prior to the twentieth century proposes an origin for the more widespread movements to follow. Druker’s subsequent chapter analyzes the crossover between Swedish artist Nerman’s children’s books and his avant-garde work in caricature art and performance, suggesting that this points to a modernism in Swedish children’s literature that precedes Astrid Lindgren and Tove Jansson. Albert, meanwhile, examines Hungarian artist Bortnyik’s only children’s book, Potty és Pötty, theorizing how this originally wordless text is illustrative of the relationship between modernism and graphic design in interwar Europe. In comparison with the single-artist focus of the earlier chapters, Reynolds offers a more expansive analysis of early [End Page 231] avant-garde publishing in Britain, suggesting that the forgotten works of Jean de Bosschére, Enid Bagnold, and Edith Saunders represent a “romantic Modernism” that contrasts to the historically perceived conservatism of British children’s literature of the time. Part 2, “The impact of the Russian avant-garde,” highlights this movement’s influence, both at home and abroad, on children’s literature from the 1920s through the 1940s. Sara Pankenier Weld’s excellent study of the avant-garde infantile begins this section, demonstrating how the minimalist suprematism of Kazimir Malevich can be usefully aligned with works for children by El Lissitzky, Vladimir Lebedev, and Vladimir Mayakovsky. Serge-Aljosja Stommels and Albert Lemmens follow with the most catalog-oriented chapter in the book, an overview of early Soviet Union children’s publishing followed by a reconstruction and assessment of the landmark 1929 Amsterdam exhibition of Soviet picture books. Nina Christensen’s chapter similarly explores the outside influence of the Russian avant-garde on four progressive Danish picture books of the 1930s and ‘40s, all the while stressing that this new model of Scandinavian children’s book was inspired by multiple cultural sources—and thereby marking its development as more than a direct offshoot of the Soviet model...