The units of DNA replication in the mammalian chromosomes: Evidence for a large size of replication units

Yurov, Yuri B.; Ляпунова, Н. А.

doi:10.1007/bf00329774

Cited by 42 publications

(29 citation statements)

References 14 publications

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“…Indeed, the fixed terminators of the replicons would not be suitable for describing the putative variable termination sites within the N-domains. The length of the N-domains matches the large, ∼1 Mbp-long replicons (Yurov and Liapunova 1977;Berezney et al 2000) rather than the usually 50-300 kbplong replicons (Edenberg and Huberman 1975), and is consistent with the large replication units observed in meiotic chromosomes (Callan 1972). In somatic cells, additional origins may be activated within the N-domains, thus leading to the commonly observed shorter replication units.…”

Section: Discussionsupporting

confidence: 77%

Human gene organization driven by the coordination of replication and transcription

et al. 2007

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In this work, we investigated a large-scale organization of the human genes with respect to putative replication origins. We developed an appropriate multiscale method to analyze the nucleotide compositional skew along the genome and found that in more than one-quarter of the genome, the skew profile presents characteristic patterns consisting of successions of N-shaped structures, designated here N-domains, bordered by putative replication origins. Our analysis of recent experimental timing data confirmed that, in a number of cases, domain borders coincide with replication initiation zones active in the early S phase, whereas the central regions replicate in the late S phase. Around the putative origins, genes are abundant and broadly expressed, and their transcription is co-oriented with replication fork progression. These features weaken progressively with the distance from putative replication origins. At the center of domains, genes are rare and expressed in few tissues. We propose that this specific organization could result from the constraints of accommodating the replication and transcription initiation processes at chromatin level, and reducing head-on collisions between the two machineries. Our findings provide a new model of gene organization in the human genome, which integrates transcription, replication, and chromatin structure as coordinated determinants of genome architecture.

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Section: Discussionsupporting

confidence: 77%

Human gene organization driven by the coordination of replication and transcription

et al. 2007

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“…skew profiles revealed a portrait of germ-line replication, consisting of putative origins separated by long DNA segments Ϸ1-2 Mbp long. Although such segments are much larger than could be expected from the classical view of Ϸ50-to 300-kbp-long replicons (37), they are not incompatible with estimations showing that replicon size can reach up to 1 Mbp (38,39) and that replicating units in meiotic chromosomes are much longer than those engaged in somatic cells (40). Finally, it is not unlikely that in GϩC-rich (gene-rich) regions, replication origins would be closer to each other than in other regions, further explaining the greater difficulty in detecting origins in these regions.…”

Section: Detection Of Putative Replication Originsmentioning

confidence: 84%

Replication-associated strand asymmetries in mammalian genomes: Toward detection of replication origins

Touchon

Nicolay

Audit

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

136

135

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In the course of evolution, mutations do not affect both strands of genomic DNA equally. This imbalance mainly results from asymmetric DNA mutation and repair processes associated with replication and transcription. In prokaryotes, prevalence of G over C and T over A is frequently observed in the leading strand. The sign of the resulting TA and GC skews changes abruptly when crossing replication-origin and termination sites, producing characteristic step-like transitions. In mammals, transcription-coupled skews have been detected, but so far, no bias has been associated with replication. Here, analysis of intergenic and transcribed regions flanking experimentally identified human replication origins and the corresponding mouse and dog homologous regions demonstrates the existence of compositional strand asymmetries associated with replication. Multiscale analysis of human genome skew profiles reveals numerous transitions that allow us to identify a set of 1,000 putative replication initiation zones. Around these putative origins, the skew profile displays a characteristic jagged pattern also observed in mouse and dog genomes. We therefore propose that in mammalian cells, replication termination sites are randomly distributed between adjacent origins. Taken together, these analyses constitute a step toward genome-wide studies of replication mechanisms.replication termination ͉ wavelet transform ͉ compositional bias ͉ skewness C omprehensive knowledge of genome evolution relies on understanding mutational processes that shape DNA sequences. Nucleotide substitutions do not occur at similar rates, and, in particular, owing to strand asymmetries of the DNA mutation and repair processes, they can affect each of the two DNA strands differently. Asymmetries of substitution rates coupled to transcription have been observed in prokaryotes (1-3) and in eukaryotes (4-6). Strand asymmetries (i.e., G C and T A) associated with the polarity of replication have been found in bacterial, mitochondrial, and viral genomes, where they have been used to detect replication origins (7-9). In most cases, the leading replicating strand presents an excess of G over C and of T over A. Along one DNA strand, the sign of this bias changes abruptly at the replication origin and at the terminus. In eukaryotes, the situation is unclear. Several studies failed to show compositional biases related to replication, and analyses of nucleotide substitutions in the region of the ␤-globin replication origin did not support the existence of mutational bias between the leading and the lagging strands (8, 10, 11). In contrast, strand asymmetries associated with replication were observed in the subtelomeric regions of Saccharomyces cerevisiae chromosomes, supporting the existence of replication-coupled asymmetric mutational pressure in this organism (12). Here, we present analyses of strand asymmetries flanking experimentally determined human replication origins, as well as the corresponding mouse and dog homologous regions. Our results demonstrate the exis...

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“…They were therefore either transition zones or late-replicated domains in which forks progressed in a single direction away from a transition zone. Further confirmation of the existence of large replicons, greater than 1 Mb in size, was obtained by the pioneering experiments of Yrov and Liapunova in 1977, in which stretched DNA molecules were labelled with 3 H-thymidine and subjected to autoradiography (Yurov and Liapunova 1977). All the experiments carried out in different systems and with different methods suggest that a fraction of the genome lacks potential sites of replication initiation.…”

Section: The Genome Contains Large Regions Devoid Of Strong Origins mentioning

confidence: 90%

Genome-wide approaches to determining origin distribution

Cadoret

Prioleau

2009

Chromosome Res

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Genome integrity depends upon a highly co-ordinated process that ensures the exact duplication of the genome at each cell cycle. Genomic mapping of DNA replication starting points in mammals, known as origins of replication, is an important step towards our understanding of how this essential mechanism is regulated throughout complex genomes. Two recent studies carried out in both human and mouse cells have revealed a strong association between replication origins and transcriptional regulatory elements. This strong overlap raises the question of how gene deserts, also lacking replication origins, are properly replicated in conditions where replication is disrupted. It also provides valuable information forward the identification of key regulatory factors of DNA replication initiation. Here, we review what these large-scale mappings of replication origins have brought to our understanding of replication initiation and what are the future prospects.

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The units of DNA replication in the mammalian chromosomes: Evidence for a large size of replication units

Cited by 42 publications

References 14 publications

Human gene organization driven by the coordination of replication and transcription

Human gene organization driven by the coordination of replication and transcription

Replication-associated strand asymmetries in mammalian genomes: Toward detection of replication origins

Genome-wide approaches to determining origin distribution

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