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Review
. 2012 Jun;22(3):204-10.
doi: 10.1016/j.gde.2012.01.009. Epub 2012 Feb 23.

Replication stress and mechanisms of CNV formation

Martin F Arlt  1 , Thomas E Wilson, Thomas W Glover
Affiliations
Review

Replication stress and mechanisms of CNV formation

Martin F Arlt et al. Curr Opin Genet Dev. 2012 Jun.

Abstract

Copy number variants (CNVs) are widely distributed throughout the human genome, where they contribute to genetic variation and phenotypic diversity. De novo CNVs are also a major cause of numerous genetic and developmental disorders. However, unlike many other types of mutations, little is known about the genetic and environmental risk factors for new and deleterious CNVs. DNA replication errors have been implicated in the generation of a major class of CNVs, the nonrecurrent CNVs. We have found that agents that perturb normal replication and create conditions of replication stress, including hydroxyurea and aphidicolin, are potent inducers of nonrecurrent CNVs in cultured human cells. These findings have broad implications for identifying CNV risk factors and for hydroxyurea-related therapies in humans.

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Figures

Figure 1
Figure 1
Possible mechanisms involved in the prevention and formation of nonrecurrent CNVs. Exposure of cells to conditions that cause replication stress will result in stalled replication, which in turn might lead to fork collapse and result in a single-ended double strand break (Top). Either of these structures will activate a number of DNA damage checkpoint and repair pathways, which should faithfully restore replication at the site of the stalled or collapsed fork (Left). These checkpoint and repair pathways serve to protect the integrity of the genome, preventing the formation of CNVs and other structural variants. However, stalled replication or collapsed replication forks could also lead to restart or repair via alternate pathways. A stalled fork may be inaccurately restarted at a distant site, using a template switching or MMBIR pathway, giving rise to a CNV. Long range end-joining of two distant DNA breaks could also lead to deletions of large amounts of intervening sequence, resulting in a CNV (Right). It is expected that mutations that inhibit a cell’s ability to properly respond to a stalled or collapsed fork will result in an increased CNV frequency
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