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Replication in context: dynamic regulation of DNA replication patterns in metazoans

Nature Reviews Genetics volume 8, pages 588–600 (2007)Cite this article

Key Points

  • In metazoa, the entire genome can replicate once each cell cycle without requiring that replication initiate from particular sequences, suggesting that the role of discrete replication initiation programmes is to coordinate replication with gene expression and chromosome condensation.

  • Specific sequences (replicators) determine the ability to initiate DNA replication in cis.

  • The likelihood of initiation from a particular replicator at a specific time during the cell cycle can be modulated by distal sequences and epigenetic modifications.

  • The location of initiation events is affected by distal sequences that often also affect transcription.

  • The location and timing of initiation events often vary with transcription but it is unclear whether the movement of the transcriptional machinery can, by itself, determine initiation sites.

  • Enzymes that modify chromatin, and proteins that recruit such enzymes to particular genomic loci, can affect the location and the timing of initiation events.

  • In certain organisms, the initiation of DNA replication is not limited to specific regions during early embryogenesis; such regions are specified later in development concurrent with chromatin remodelling.

  • Differentiation of specific cell lineages often alters the location and timing of replication initiation in certain loci, concomitant with changes in gene expression.

  • Flexibility in the location and timing of initiation events might help maintain an appropriate number of replication forks during S phase to help preserve genomic stability.

Abstract

Replication in eukaryotes initiates from discrete genomic regions according to a strict, often tissue-specific temporal programme. However, the locations of initiation events within initiation regions vary, show sequence disparity and are affected by interactions with distal elements. Increasing evidence suggests that specification of replication sites and the timing of replication are dynamic processes that are regulated by tissue-specific and developmental cues, and are responsive to epigenetic modifications. Dynamic specification of replication patterns might serve to prevent or resolve possible spatial and/or temporal conflicts between replication, transcription and chromatin assembly, and facilitate subtle or extensive changes of gene expression during differentiation and development.

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Figure 1: Assembly of pre-replication and pre-initiation protein complexes.
Figure 2: Confined and extended replication initiation regions.
Figure 3: Distal elements affecting where and when replication initiates.
Figure 4: Variations of replication patterns during differentiation and in response to metabolic changes.

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Acknowledgements

The author wishes to thank F. Antequera, O. Aparicio, G. Biamonti, A. Bielinsky, W. Burhans, B. Calvi, M. DePamphilis, A. Dutta, A. Falaschi, S. Gerbi, M. Giacca, D. Gilbert, J. Hamlin, J. Huberman, O. Hyrien, G. Kapler, J. Lee, E. Fanning, T. Kelly, M. Leffak, D. Livingston, M. Mechali, S. Miyatake, C. Pearson, M-N. Prioleau, Y. Pommier, N. Rhind, C. Schildkraut, M. Thayer, J. Tower, K. Tsutsumi, J. Walter and M. Zannis-Hadjopoulos, who shared unpublished data or discussed pertinent issues, and to apologize to those whose primary work could not be cited directly due to space restrictions. Research in the author's laboratory is supported by the Intramural Research Program of the US National Cancer Institute, Centre for Cancer Research, National Institutes of Health.

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    Mirit I. Aladjem

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Glossary

Epigenetic

A mitotically stable change in gene expression that depends not on a change in DNA sequence, but on covalent modifications of DNA or chromatin proteins such as histones.

Replication licensing

A process that allows chromatin to become competent for DNA synthesis during the G1 phase of the cell cycle by the ordered loading of proteins (including the origin recognition complex (ORC) and minichromosome maintenance (MCM) complexes, CDC6 and CDT1) to form pre-replication complexes. In mitotic cells, several mechanisms prevent licensing between the onset of S phase and the completion of mitosis to restrict replication to once in a cell cycle.

Matrix attachment site

Also known as a scaffold attachment site. A region of DNA that is attached to the nuclear matrix, a network of fibrous proteins that contributes to nuclear organization.

CpG island

Sequences of 200 bp or more that have high GC content and a high frequency of CpG dinucleotides. CpG islands are found upstream of many mammalian genes.

DNase I hypersensitive site

A chromosomal region that is highly accessible to cleavage by DNase I. Such sites are associated with open chromatin conformations and transcriptional activity.

Histone modifications

Post-translational modifications of histone tails involve characteristic clusters of modifications, including acetylation, phosphorylation, ubiquitylation, methylation and ADP-ribosylation, which combine to create an epigenetic mechanism for the regulation of gene expression.

Histone variants

A family of genes encoding multiple non-allelic primary-sequence variants of histone proteins. Some histone variants have specialized functions in gene regulation, damage recognition or labelling of specific chromatin regions such as centromeres.

Nucleosome

The fundamental unit into which DNA and histones are packaged in eukaryotic cells. It is the basic structural subunit of chromatin and consists of 200 bp of DNA and an octamer of histone proteins, comprising two of each core histone.

Heterochromatin

Chromosomal material that is tightly coiled and inactive in terms of gene expression.

Euchromatin

The lightly staining regions that generally contain decondensed, transcriptionally active regions of the genome.

Imprinted genes

Refers to the epigenetic marking of a locus on the basis of parental origin, which results in monoallelic gene expression.

Mid-blastula transition

A stage during embryogenesis when zygotic transcription starts and cell divisions become asynchronous.

Endoreplication

Repeated replication of genomic DNA during the S phase of the cell cycle without the subsequent completion of mitosis and/or cytokinesis. Endoreplication results in polyploidy (cells with more than two haploid sets of chromosomes, for example, megakaryocytes and trophoblast cells) or polyteny (large, multistranded chromosomes, for example, in cells of several insects' salivary glands).

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Aladjem, M. Replication in context: dynamic regulation of DNA replication patterns in metazoans. Nat Rev Genet 8, 588–600 (2007). https://doi.org/10.1038/nrg2143

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