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Replicating by the clock

Nature Reviews Molecular Cell Biology volume 4, pages 25–32 (2003)Cite this article

Key Points

  • The genome is organized into distinct 1–2 Mb bands that contain numerous origins, which are coordinated to replicate in a programmed manner during S phase. These bands represent subunits of chromosome structure and function.

  • There is a general correlation between replication timing and gene expression. Housekeeping genes replicate early in S phase, whereas many tissue-specific genes are developmentally regulated — they replicate late in most cell types and early in the tissue of expression.

  • Genes that are expressed monoallelically replicate asynchronously in S phase, with one allele copied earlier than the other. This mechanism functions as an epigenetic mark for distinguishing between the alleles, and it is used both for genomic imprinting and for setting up allelic exclusion in the immune system and at olfactory-receptor gene loci. Asynchronous replication timing at several regions on each autosome is coordinated, and this might be carried out by individual control centres in a way that is similar to X inactivation.

  • The genomic replication-timing pattern is set up during the G1 stage of the cell cycle through interactions between cis-acting sequences and trans-acting factors that bring about epigenetic changes that have an impact on the firing of nearby replication origins during S phase. This process is probably controlled by cell-cycle-regulated factors.

  • Late replication might function as a mechanism for maintaining gene repression through many cell generations by causing DNA to be repackaged with deacetylated histones after passage through the replication fork. By contrast, early-replicating DNA is assembled with acetylated histones. In this way, replication time might influence gene accessibility.

Abstract

The eukaryotic genome is divided into well-defined DNA regions that are programmed to replicate at different times during S phase. Active genes are generally associated with early replication, whereas inactive genes replicate late. This expression pattern might be facilitated by the differential restructuring of chromatin at the time of replication in early or late S phase.

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Figure 1: Replication bands.
Figure 2: FISH analysis of monoallelically expressed genes.
Figure 3: Control of replication timing.
Figure 4: Chromatin formation in early and late S phase — a model.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, the Israel Cancer Research Fund and the Israel Science Foundation.

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Authors and Affiliations

  1. Department of Cellular Biochemistry and Human Genetics, Hebrew University, Ein Kerem, Jerusalem, 91120, Israel

    Alon Goren & Howard Cedar

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  1. Alon Goren
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Correspondence to Howard Cedar.

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DATABASES

LocusLink

β-globin

CFTR

OMIM

Angelman syndrome

Prader–Willi syndrome

Saccharomyces Genome Database

HML

HMR

MAT

Swiss-Prot

Clb5

HAT

HDAC2

Ku

Mec1

Rad53

Sir3

FURTHER INFORMATION

Howard Cedar's laboratory

Glossary

G BANDS

A characteristic chromosome-banding pattern that is shown by staining with Giemsa. Light and dark G bands differ in their molecular and regulatory features, such as gene density, repetitive sequence elements and replication timing.

ISOCHORES

Long DNA fragments (>300 kb) defined by their average G+C content. Isochores are divided into five subfamilies according to their G+C composition: from G+C poor (∼40% G+C) to G+C rich (∼55–60% G+C).

EPIGENETIC

Any heritable influence on the function of a chromosome or gene that is not caused by a change in DNA sequence.

X-CHROMOSOME INACTIVATION

The transcriptional inactivation of one of the two X chromosomes in female embryos. The choice of the maternal or the paternal allele is random, but is then maintained clonally in subsequent cell generations. The inactive X chromosome is characterized by DNA methylation, late replication timing and condensed chromatin structure.

X-INACTIVATION CENTRE

(Xic). A cis-acting region on the X chromosome that produces the X-inactivation-specific transcript (Xist) that is necessary for initiating X-chromosome inactivation in female cells.

ALLELIC EXCLUSION

The process by which a cell (for example, from the immune or olfactory system) uses either the gene from its maternal chromosome or the one from the paternal chromosome, but not both.

LOCUS CONTROL REGION

(LCR). A large regulatory sequence that harbours several elements that control gene expression and chromatin structure during development.

CHECKPOINT

A point at which the cell-division cycle can be halted until conditions are suitable for the cell to proceed to the next stage.

HETEROCHROMATIN

A cytologically defined genomic component that contains repetitive DNA (highly repetitive satellite DNA, transposable elements and ribosomal DNA gene clusters) and some protein-encoding genes.

HISTONE ACETYLTRANSFERASE

(HAT). An enzyme that modifies histone tails covalently by adding an acetyl group to lysine residues, thereby changing their structure.

CHROMATIN IMMUNOPRECIPITATION

(ChIP). A technique that isolates sequences from soluble DNA chromatin extracts (complexes of DNA and protein) by using antibodies that recognize specific chromosomal proteins.

CPG ISLANDS

Sequences (0.5–2 kb) that are rich in the CpG dinucleotide, which are mostly located upstream to housekeeping and some tissue-specific genes. They are constitutively non-methylated in all animal cell types.

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Goren, A., Cedar, H. Replicating by the clock. Nat Rev Mol Cell Biol 4, 25–32 (2003). https://doi.org/10.1038/nrm1008

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