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David M Gilbert - One of the best experts on this subject based on the ideXlab platform.
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Mammalian DNA Replication Timing.
Cold Spring Harbor perspectives in biology, 2021Co-Authors: Athanasios E. Vouzas, David M GilbertAbstract:Immediately following the discovery of the structure of DNA and the semi-conservative Replication of the parental DNA sequence into two new DNA strands, it became apparent that DNA Replication is organized in a temporal and spatial fashion during the S phase of the cell cycle, correlated with the large-scale organization of chromatin in the nucleus. After many decades of limited progress, technological advances in genomics, genome engineering, and imaging have finally positioned the field to tackle mechanisms underpinning the temporal and spatial regulation of DNA Replication and the causal relationships between DNA Replication and other features of large-scale chromosome structure and function. In this review, we discuss these major recent discoveries as well as expectations for the coming decade.
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3d genome organization contributes to genome instability at fragile sites
Nature Communications, 2020Co-Authors: Dan Sarni, Takayo Sasaki, Michal Irony Tursinai, Karin Miron, Juan Carlos Riveramulia, Brian Magnuson, Mats Ljungman, David M Gilbert, Batsheva KeremAbstract:Common fragile sites (CFSs) are regions susceptible to Replication stress and are hotspots for chromosomal instability in cancer. Several features were suggested to underlie CFS instability, however, these features are prevalent across the genome. Therefore, the molecular mechanisms underlying CFS instability remain unclear. Here, we explore the transcriptional profile and DNA Replication Timing (RT) under mild Replication stress in the context of the 3D genome organization. The results reveal a fragility signature, comprised of a TAD boundary overlapping a highly transcribed large gene with APH-induced RT-delay. This signature enables precise mapping of core fragility regions in known CFSs and identification of novel fragile sites. CFS stability may be compromised by incomplete DNA Replication and repair in TAD boundaries core fragility regions leading to genomic instability. The identified fragility signature will allow for a more comprehensive mapping of CFSs and pave the way for investigating mechanisms promoting genomic instability in cancer.
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Control of DNA Replication Timing in the 3D genome
Nature Reviews Molecular Cell Biology, 2019Co-Authors: Claire Marchal, Jiao Sima, David M GilbertAbstract:The 3D organization of mammalian chromatin was described more than 30 years ago by visualizing sites of DNA synthesis at different times during the S phase of the cell cycle. These early cytogenetic studies revealed structurally stable chromosome domains organized into subnuclear compartments. Active-gene-rich domains in the nuclear interior replicate early, whereas more condensed chromatin domains that are largely at the nuclear and nucleolar periphery replicate later. During the past decade, this spatiotemporal DNA Replication programme has been mapped along the genome and found to correlate with epigenetic marks, transcriptional activity and features of 3D genome architecture such as chromosome compartments and topologically associated domains. But the causal relationship between these features and DNA Replication Timing and the regulatory mechanisms involved have remained an enigma. The recent identification of cis -acting elements regulating the Replication time and 3D architecture of individual Replication domains and of long non-coding RNAs that coordinate whole chromosome Replication provide insights into such mechanisms. Different genomic regions are replicated at different times during the S phase of the cell cycle, forming early- and late-replicating domains that occupy different locations in the nucleus. The recent identification of specific DNA sequences and long non-coding RNAs that regulate DNA Replication Timing is providing key insights into the roles of Replication Timing and into Timing and 3D organization.
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Cellular senescence induces Replication stress with almost no affect on DNA Replication Timing.
Cell cycle (Georgetown Tex.), 2018Co-Authors: Juan Carlos Rivera-mulia, Romain Desprat, Claudia Trevilla-garcia, Jiao Sima, Helene Schwerer, David M Gilbert, Emilie Besnard, Paul Bensadoun, Anissa Zouaoui, Jean-marc LemaitreAbstract:Organismal aging entails a gradual decline of normal physiological functions and a major contributor to this decline is withdrawal of the cell cycle, known as senescence. Senescence can result from telomere diminution leading to a finite number of population doublings, known as replicative senescence (RS), or from oncogene overexpression, as a protective mechanism against cancer. Senescence is associated with large-scale chromatin re-organization and changes in gene expression. Replication stress is a complex phenomenon, defined as the slowing or stalling of Replication fork progression and/or DNA synthesis, which has serious implications for genome stability, and consequently in human diseases. Aberrant Replication fork structures activate the Replication stress response leading to the activation of dormant origins, which is thought to be a safeguard mechanism to complete DNA Replication on time. However, the relationship between replicative stress and the changes in the spatiotemporal program of DNA Replication in senescence progression remains unclear. Here, we studied the DNA Replication program during senescence progression in proliferative and pre-senescent cells from donors of various ages by single DNA fiber combing of replicated DNA, origin mapping by sequencing short nascent strands and genome-wide profiling of Replication Timing (TRT). We demonstrate that, progression into RS leads to reduced Replication fork rates and activation of dormant origins, which are the hallmarks of Replication stress. However, with the exception of a delay in RT of the CREB5 gene in all pre-senescent cells, RT was globally unaffected by Replication stress during entry into either oncogene-induced or RS. Consequently, we conclude that RT alterations associated with physiological and accelerated aging, do not result from senescence progression. Our results clarify the interplay between senescence, aging and Replication programs and demonstrate that RT is largely resistant to Replication stress.
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DNA Replication Timing
Cold Spring Harbor Perspectives in Biology, 2013Co-Authors: Nick Rhind, David M GilbertAbstract:Patterns of Replication within eukaryotic genomes correlate with gene expression, chromatin structure, and genome evolution. Recent advances in genome-scale mapping of Replication kinetics have allowed these correlations to be explored in many species, cell types, and growth conditions, and these large data sets have allowed quantitative and computational analyses. One striking new correlation to emerge from these analyses is between Replication Timing and the three-dimensional structure of chromosomes. This correlation, which is significantly stronger than with any single histone modification or chromosome-binding protein, suggests that Replication Timing is controlled at the level of chromosomal domains. This conclusion dovetails with parallel work on the heterogeneity of origin firing and the competition between origins for limiting activators to suggest a model in which the stochastic probability of individual origin firing is modulated by chromosomal domain structure to produce patterns of Replication. Whether these patterns have inherent biological functions or simply reflect higher-order genome structure is an open question.
Jianhua Liu - One of the best experts on this subject based on the ideXlab platform.
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near sigmoid modeling to simultaneously profile genome wide DNA Replication Timing and efficiency in single DNA Replication microarray studies
Asia-Pacific Bioinformatics Conference, 2007Co-Authors: Majid Eshaghi, Jianhua Liu, Karuturi Krishna R MurthyAbstract:DNA Replication is a key process in cell division cycle. It is initiated in coordinated manner in several species. To understand the DNA Replication in a species one needs to measure the half Replication Timing (or Replication Timing) and the efficiency of Replication which vary across genome in higher eukaryotes. In the previous studies, no direct assessment of Replication efficiency on a genomic scale was performed while the Replication Timing was indirectly assessed using average DNA. In this paper, we present a first-ever-method of directly measuring both half Replication Timing and efficiency simultaneously from a single DNA microarray time-course data. We achieve it by fitting the so called near-sigmoid model to each locus of the DNA. We use this model apply S. pombe DNA Replication microarray data and show that it is effective for genome-scale Replication Timing and efficiency profiling studies.
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Global Profiling of DNA Replication Timing and Efficiency Reveals that Efficient Replication/Firing Occurs Late during S-Phase in S. pombe
PloS one, 2007Co-Authors: Majid Eshaghi, R. Krishna Murthy Karuturi, Zhaoqing Chu, Edison T. Liu, Jianhua LiuAbstract:Background During S. pombe S-phase, initiation of DNA Replication occurs at multiple sites (origins) that are enriched with AT-rich sequences, at various times. Current studies of genome-wide DNA Replication profiles have focused on the DNA Replication Timing and origin location. However, the Replication and/or firing efficiency of the individual origins on the genomic scale remain unclear.
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global profiling of DNA Replication Timing and efficiency reveals that efficient Replication firing occurs late during s phase in s pombe
PLOS ONE, 2007Co-Authors: Majid Eshaghi, Zhaoqing Chu, Edison T. Liu, Jianhua Liu, Krishna Murthy R KaruturiAbstract:Background During S. pombe S-phase, initiation of DNA Replication occurs at multiple sites (origins) that are enriched with AT-rich sequences, at various times. Current studies of genome-wide DNA Replication profiles have focused on the DNA Replication Timing and origin location. However, the Replication and/or firing efficiency of the individual origins on the genomic scale remain unclear.
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APBC - Near-sigmoid Modeling to Simultaneously Profile Genome-wide DNA Replication Timing and Efficiency in Single DNA Replication Microarray Studies.
Proceedings of the 6th Asia-Pacific Bioinformatics Conference, 2007Co-Authors: Majid Eshaghi, Jianhua Liu, Karuturi R. Krishna MurthyAbstract:DNA Replication is a key process in cell division cycle. It is initiated in coordinated manner in several species. To understand the DNA Replication in a species one needs to measure the half Replication Timing (or Replication Timing) and the efficiency of Replication which vary across genome in higher eukaryotes. In the previous studies, no direct assessment of Replication efficiency on a genomic scale was performed while the Replication Timing was indirectly assessed using average DNA. In this paper, we present a first-ever-method of directly measuring both half Replication Timing and efficiency simultaneously from a single DNA microarray time-course data. We achieve it by fitting the so called near-sigmoid model to each locus of the DNA. We use this model apply S. pombe DNA Replication microarray data and show that it is effective for genome-scale Replication Timing and efficiency profiling studies.
Majid Eshaghi - One of the best experts on this subject based on the ideXlab platform.
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near sigmoid modeling to simultaneously profile genome wide DNA Replication Timing and efficiency in single DNA Replication microarray studies
Asia-Pacific Bioinformatics Conference, 2007Co-Authors: Majid Eshaghi, Jianhua Liu, Karuturi Krishna R MurthyAbstract:DNA Replication is a key process in cell division cycle. It is initiated in coordinated manner in several species. To understand the DNA Replication in a species one needs to measure the half Replication Timing (or Replication Timing) and the efficiency of Replication which vary across genome in higher eukaryotes. In the previous studies, no direct assessment of Replication efficiency on a genomic scale was performed while the Replication Timing was indirectly assessed using average DNA. In this paper, we present a first-ever-method of directly measuring both half Replication Timing and efficiency simultaneously from a single DNA microarray time-course data. We achieve it by fitting the so called near-sigmoid model to each locus of the DNA. We use this model apply S. pombe DNA Replication microarray data and show that it is effective for genome-scale Replication Timing and efficiency profiling studies.
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Global Profiling of DNA Replication Timing and Efficiency Reveals that Efficient Replication/Firing Occurs Late during S-Phase in S. pombe
PloS one, 2007Co-Authors: Majid Eshaghi, R. Krishna Murthy Karuturi, Zhaoqing Chu, Edison T. Liu, Jianhua LiuAbstract:Background During S. pombe S-phase, initiation of DNA Replication occurs at multiple sites (origins) that are enriched with AT-rich sequences, at various times. Current studies of genome-wide DNA Replication profiles have focused on the DNA Replication Timing and origin location. However, the Replication and/or firing efficiency of the individual origins on the genomic scale remain unclear.
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global profiling of DNA Replication Timing and efficiency reveals that efficient Replication firing occurs late during s phase in s pombe
PLOS ONE, 2007Co-Authors: Majid Eshaghi, Zhaoqing Chu, Edison T. Liu, Jianhua Liu, Krishna Murthy R KaruturiAbstract:Background During S. pombe S-phase, initiation of DNA Replication occurs at multiple sites (origins) that are enriched with AT-rich sequences, at various times. Current studies of genome-wide DNA Replication profiles have focused on the DNA Replication Timing and origin location. However, the Replication and/or firing efficiency of the individual origins on the genomic scale remain unclear.
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APBC - Near-sigmoid Modeling to Simultaneously Profile Genome-wide DNA Replication Timing and Efficiency in Single DNA Replication Microarray Studies.
Proceedings of the 6th Asia-Pacific Bioinformatics Conference, 2007Co-Authors: Majid Eshaghi, Jianhua Liu, Karuturi R. Krishna MurthyAbstract:DNA Replication is a key process in cell division cycle. It is initiated in coordinated manner in several species. To understand the DNA Replication in a species one needs to measure the half Replication Timing (or Replication Timing) and the efficiency of Replication which vary across genome in higher eukaryotes. In the previous studies, no direct assessment of Replication efficiency on a genomic scale was performed while the Replication Timing was indirectly assessed using average DNA. In this paper, we present a first-ever-method of directly measuring both half Replication Timing and efficiency simultaneously from a single DNA microarray time-course data. We achieve it by fitting the so called near-sigmoid model to each locus of the DNA. We use this model apply S. pombe DNA Replication microarray data and show that it is effective for genome-scale Replication Timing and efficiency profiling studies.
Amnon Koren - One of the best experts on this subject based on the ideXlab platform.
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TIGER: inferring DNA Replication Timing from whole-genome sequence data.
Bioinformatics (Oxford England), 2021Co-Authors: Amnon Koren, Dashiell J Massey, Alexa N. BracciAbstract:MOTIVATION Genomic DNA replicates according to a reproducible spatiotemporal program, with some loci replicating early in S phase while others replicate late. Despite being a central cellular process, DNA Replication Timing studies have been limited in scale due to technical challenges. RESULTS We present TIGER (Timing Inferred from Genome Replication), a computational approach for extracting DNA Replication Timing information from whole genome sequence data obtained from proliferating cell samples. The presence of replicating cells in a biological specimen leads to non-uniform representation of genomic DNA that depends on the Timing of Replication of different genomic loci. Replication dynamics can hence be observed in genome sequence data by analyzing DNA copy number along chromosomes while accounting for other sources of sequence coverage variation. TIGER is applicable to any species with a contiguous genome assembly and rivals the quality of experimental measurements of DNA Replication Timing. It provides a straightforward approach for measuring Replication Timing and can readily be applied at scale. AVAILABILITY AND IMPLEMENTATION TIGER is available at https://github.com/TheKorenLab/TIGER. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Germline Structural Variations Are Preferential Sites of DNA Replication Timing Plasticity during Development.
Genome biology and evolution, 2019Co-Authors: Michelle L Hulke, Christopher L. Sansam, Joseph C. Siefert, Amnon KorenAbstract:The DNA Replication Timing program is modulated throughout development and is also one of the main factors influencing the distribution of mutation rates across the genome. However, the relationship between the mutagenic influence of Replication Timing and its developmental plasticity remains unexplored. Here, we studied the distribution of copy number variations (CNVs) and single nucleotide polymorphisms across the zebrafish genome in relation to changes in DNA Replication Timing during embryonic development in this model vertebrate species. We show that CNV sites exhibit strong Replication Timing plasticity during development, replicating significantly early during early development but significantly late during more advanced developmental stages. Reciprocally, genomic regions that changed their Replication Timing during development contained a higher proportion of CNVs than developmentally constant regions. Developmentally plastic CNV sites, in particular those that become delayed in their Replication Timing, were enriched for the clustered protocadherins, a set of genes important for neuronal development that have undergone extensive genetic and epigenetic diversification during zebrafish evolution. In contrast, single nucleotide polymorphism sites replicated consistently early throughout embryonic development, highlighting a unique aspect of the zebrafish genome. Our results uncover a hitherto unrecognized interface between development and evolution.
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Profiling DNA Replication Timing Using Zebrafish as an In Vivo Model System.
Journal of visualized experiments : JoVE, 2018Co-Authors: Joseph C. Siefert, Amnon Koren, Emily A. Clowdus, Duane Goins, Christopher L. SansamAbstract:DNA Replication Timing is an important cellular characteristic, exhibiting significant relationships with chromatin structure, transcription, and DNA mutation rates. Changes in Replication Timing occur during development and in cancer, but the role Replication Timing plays in development and disease is not known. Zebrafish were recently established as an in vivo model system to study Replication Timing. Here is detailed the protocols for using the zebrafish to determine DNA Replication Timing. After sorting cells from embryos and adult zebrafish, high-resolution genome-wide DNA Replication Timing patterns can be constructed by determining changes in DNA copy number through analysis of next generation sequencing data. The zebrafish model system allows for evaluation of the Replication Timing changes that occur in vivo throughout development, and can also be used to assess changes in individual cell types, disease models, or mutant lines. These methods will enable studies investigating the mechanisms and determinants of Replication Timing establishment and maintenance during development, the role Replication Timing plays in mutations and tumorigenesis, and the effects of perturbing Replication Timing on development and disease.
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DNA Replication Timing during development anticipates transcriptional programs and parallels enhancer activation.
Genome research, 2017Co-Authors: Joseph C. Siefert, Amnon Koren, Constantin Georgescu, Jonathan D. Wren, Christopher L. SansamAbstract:In dividing cells, DNA Replication occurs in a precise order, but many questions remain regarding the mechanisms of Replication Timing establishment and regulation. We now have generated genome-wide, high-resolution Replication Timing maps throughout zebrafish development. Unexpectedly, in the rapid cell cycles preceding the midblastula transition, a defined Timing program was present that predicted the initial wave of zygotic transcription. Replication Timing was thereafter progressively and continuously remodeled across the majority of the genome, and epigenetic changes involved in enhancer activation frequently paralleled developmental changes in Replication Timing. The long arm of Chromosome 4 underwent a dramatic developmentally regulated switch to late Replication during gastrulation, reminiscent of mammalian X Chromosome inactivation. This study reveals that Replication Timing is dynamic and tightly linked to epigenetic and transcriptional changes throughout early zebrafish development. These data provide insight into the regulation and functions of Replication Timing and will enable further mechanistic studies.
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genetic variation in human DNA Replication Timing
Cell, 2014Co-Authors: Amnon Koren, Sulagna Ghosh, Paz Polak, Robert E Handsaker, Nolan Kamitaki, Rosa KarlicAbstract:Genomic DNA replicates in a choreographed temporal order that impacts the distribution of mutations along the genome. We show here that DNA Replication Timing is shaped by genetic polymorphisms that act in cis upon megabase-scale DNA segments. In genome sequences from proliferating cells, read depth along chromosomes reflected DNA Replication activity in those cells. We used this relationship to analyze variation in Replication Timing among 161 individuals sequenced by the 1000 Genomes Project. Genome-wide association of Replication Timing with genetic variation identified 16 loci at which inherited alleles associate with Replication Timing. We call these “Replication Timing quantitative trait loci” (rtQTLs). rtQTLs involved the differential use of Replication origins, exhibited allele-specific effects on Replication Timing, and associated with gene expression variation at megabase scales. Our results show Replication Timing to be shaped by genetic polymorphism and identify a means by which inherited polymorphism regulates the mutability of nearby sequences.
David Shore - One of the best experts on this subject based on the ideXlab platform.
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Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane.
Nature Communications, 2019Co-Authors: Gabriele A. Fontana, Julia K. Reinert, Stefano Mattarocci, Benoît Falquet, Dominique Klein, Nicolas H. Thomä, David Shore, Daniel Heß, Ulrich RassAbstract:Rif1 is involved in telomere homeostasis, DNA Replication Timing, and DNA double-strand break (DSB) repair pathway choice from yeast to human. The molecular mechanisms that enable Rif1 to fulfill its diverse roles remain to be determined. Here, we demonstrate that Rif1 is S-acylated within its conserved N-terminal domain at cysteine residues C466 and C473 by the DHHC family palmitoyl acyltransferase Pfa4. Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, the attenuation of DNA end-resection, and DSB repair by non-homologous end-joining (NHEJ). These findings identify S-acylation as a posttranslational modification regulating DNA repair. S-acylated Rif1 mounts a localized DNA-damage response proximal to the inner nuclear membrane, revealing a mechanism of compartmentalized DSB repair pathway choice by sequestration of a fatty acylated repair factor at the inner nuclear membrane.
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Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane
Nature Communications, 2019Co-Authors: Gabriele A. Fontana, Julia K. Reinert, Stefano Mattarocci, Benoît Falquet, Dominique Klein, Nicolas H. Thomä, David Shore, Daniel Heß, Ulrich RassAbstract:Rif1 is involved in different processes such as telomere homeostasis, DNA Replication Timing, and DNA double strand break (DSB) repair pathway choice. Here, the authors reveal that Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, attenuation of DNA end-resection, and DSB repair by non-homologous end-joining. Rif1 is involved in telomere homeostasis, DNA Replication Timing, and DNA double-strand break (DSB) repair pathway choice from yeast to human. The molecular mechanisms that enable Rif1 to fulfill its diverse roles remain to be determined. Here, we demonstrate that Rif1 is S -acylated within its conserved N-terminal domain at cysteine residues C466 and C473 by the DHHC family palmitoyl acyltransferase Pfa4. Rif1 S- acylation facilitates the accumulation of Rif1 at DSBs, the attenuation of DNA end-resection, and DSB repair by non-homologous end-joining (NHEJ). These findings identify S- acylation as a posttranslational modification regulating DNA repair. S -acylated Rif1 mounts a localized DNA-damage response proximal to the inner nuclear membrane, revealing a mechanism of compartmentalized DSB repair pathway choice by sequestration of a fatty acylated repair factor at the inner nuclear membrane.
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Rif1 Controls DNA Replication Timing in Yeast through the PP1 Phosphatase Glc7
Cell reports, 2014Co-Authors: Stefano Mattarocci, Nicolas H. Thomä, Maksym Shyian, Laure Lemmens, Pascal Damay, Dogus Murat Altintas, Tianlai Shi, Clinton R. Bartholomew, Christopher F.j. Hardy, David ShoreAbstract:The Rif1 protein, originally identified as a telomere-binding factor in yeast, has recently been implicated in DNA Replication control from yeast to metazoans. Here, we show that budding yeast Rif1 protein inhibits activation of preReplication complexes (pre-RCs). This inhibitory function requires two N-terminal motifs, RVxF and SILK, associated with recruitment of PP1 phosphatase (Glc7). In G1 phase, we show both that Glc7 interacts with Rif1 in an RVxF/SILK-dependent manner and that two proteins implicated in pre-RC activation, Mcm4 and Sld3, display increased Dbf4-dependent kinase (DDK) phosphorylation in rif1 mutants. Rif1 also interacts with Dbf4 in yeast two-hybrid assays, further implicating this protein in direct modulation of pre-RC activation through the DDK. Finally, we demonstrate Rif1 RVxF/SILK motif-dependent recruitment of Glc7 to telomeres and earlier Replication of these regions in cells where the motifs are mutated. Our data thus link Rif1 to negative regulation of Replication origin firing through recruitment of the Glc7 phosphatase.
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Global control of DNA Replication Timing by the budding yeast telomere protein Rif1
Epigenetics & Chromatin, 2013Co-Authors: Laure Lemmens, Stefano Mattarocci, Nicolas H. Thomä, Tianlai Shi, Isabella Marcomini, Cindy Follonier, Massimo Lopes, David ShoreAbstract:Results We showed previously that telomere TG-repeat tract length exerts an epigenetic effect in cis on the activity of nearby subtelomeric Replication origins, such that a shortened telomere will replicate earlier [1]. Here we show that deletion of the RIF1 gene, which encodes a telomere-specific Rap1-interacting protein involved in telomere length regulation and telomere “capping” [2-5], also leads to premature Replication of two different subtelomeric regions examined. A similar effect of RIF1 deletion on other subtelomeric regions has recently been described [6]. We show here that the effect of RIF1 deletion is epistatic to loss of Tel1 or Mec1 (ATM and ATR kinases), does not affect the intra-S phase checkpoint, and operates through a different pathway than the silencing protein Sir3. Deletion of a normally dormant telomere-proximal Replication origin exerts a similar effect on Replication Timing as does deletion of RIF1, and these two effects are additive. Strikingly, deletion of RIF1 partially suppresses temperature-sensitive mutations in a number of essential genes that encode regulators of DNA Replication initiation, without affecting the levels of the relevant gene products, several of which are present in limiting amounts.