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  • Review Article
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Genome instability: a mechanistic view of its causes and consequences

Nature Reviews Genetics volume 9, pages 204–217 (2008)Cite this article

Key Points

  • Genetic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders, but it is also crucial for evolution and the generation of genetic diversity. In humans, genomic instability is often associated with premature ageing, predisposition to various types of cancer and with inherited diseases.

  • Two types of elements contribute to instability leading to rearrangements: suppressors, which function in trans and include replication, repair and S-phase checkpoint factors; and chromosomal sites, which act in cis as hotspots of instability, and include fragile sites and highly transcribed DNA sequences.

  • To preserve genome integrity and proper cell-cycle progression, eukaryotic cells have developed checkpoint functions that are constantly monitoring DNA integrity and that serve to coordinate replication with repair, chromosome segregation and cell-cycle progression. Among the cellular checkpoints, S-phase checkpoints are crucial for maintaining genome integrity as they respond to fork stalling and intra-S damage by preventing fork collapse.

  • Chromosomal rearrangements might be associated with breaks or ssDNA gaps generated by stalling and/or collapse of replication forks. This might be caused primarily by secondary DNA structures or by failure in the replication machinery, the S-phase checkpoint or the double-stranded-break repair machinery.

  • Fragile sites are specific DNA sequences that exhibit gaps, constrictions and breaks that arise following partial inhibition of DNA synthesis. They appear when replication progression is impaired, mainly at a DNA stem-loop or triplex that impairs fork progression, probably leading to fork stalling and the formation of DNA breaks that are responsible for rearrangements.

  • Transcription-associated recombination is linked to the ability of the RNA polymerase to interfere with fork progression, either by physically obstructing the fork or by promoting DNA synthesis-blocking lesions, whether or not mediated by R loops. This may also be the case for transcription-dependent AID-mediated rearrangements that involves immunoglobulin genes.

Abstract

Genomic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders, and yet it is also crucial for evolution. Two types of elements have a key role in instability leading to rearrangements: those that act in trans to prevent instability — among them are replication, repair and S-phase checkpoint factors — and those that act in cis — chromosomal hotspots of instability such as fragile sites and highly transcribed DNA sequences. Taking these elements as a guide, we review the causes and consequences of instability with the aim of providing a mechanistic perspective on the origin of genomic instability.

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Figure 1: Replication fork progression and stalling.
Figure 2: Formation of double-stranded breaks and ssDNA gaps during replication.
Figure 3: Mechanisms of double-stranded break repair leading to different chromosome rearrangements.
Figure 4: Detection of genome instability and DNA breaks.
Figure 5: Models of double-stranded break formation at fragile sites.
Figure 6: DNA intermediates that are potentially associated with transcription-associated recombination.

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Acknowledgements

We thank H. Klein, K. Myung, A. Ramiro and F. Prado for comments on the manuscript and D. Haun for style supervision. We apologize to those whose publications could not be cited owing to space limitations. Research in A.A.'s laboratory is funded by grants from the Spanish Ministry of Science and Education (BFU2006-05260), Consolider Ingenio 2010 (CDS2007-015) and Junta de Andalucía (CVI102 and CVI624).

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  1. Centro Andaluz de Biologia Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Avd. Américo Vespucio s/n, Sevilla, 41092, Spain

    Andrés Aguilera & Belén Gómez-González

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  1. Andrés Aguilera
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Correspondence to Andrés Aguilera.

Supplementary information

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A selection of eukaryotic genes with a role in the maintenance of genome integrity (PDF 343 kb)

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DATABASES

OMIM

Burkitt's lymphoma

fragile X mental retardation syndrome

Friedrich's ataxia

Huntington disease

myotonic dystrophy

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Glossary

Spindle mitotic checkpoint

A quality-control mechanism that blocks anaphase entry, arresting cell growth until all chromosomes are properly attached to the mitotic spindle to achieve their accurate segregation.

Replisome

A complex of proteins involved in DNA replication elongation that moves along the DNA as the nascent strands are synthesized.

DNA adduct

A DNA sequence that is covalently-bound to a chemical residue such as cisplatin or benzopyrene.

Loss-of-heterozygosity

(LOH). The loss of one of the alleles at a given locus as a result of a genomic change, such as mitotic deletion, gene conversion or chromosome missegregration.

Minisatellite

A class of repetitive sequences, 7–100 nucleotides each, that span 0.5–20 kb and are located throughout the genome, especially towards chromosome ends.

G loops

Structures that are formed during transcription that contain a stable mRNA–DNA hybrid on the transcribed strand and a G-quartet DNA on the Grich non-transcribed strand.

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Aguilera, A., Gómez-González, B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet 9, 204–217 (2008). https://doi.org/10.1038/nrg2268

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