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PubMed · 15851063

Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability.

John D Cleary·Christopher E Pearson
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Abstract

Gene-specific repeat instability is responsible for >36 human diseases. Active instability varies in a tissue-, developmental stage- and locus-specific manner and occurs in both proliferative and non-proliferative cells. In proliferative cells, DNA replication can contribute to repeat instability either by switching the direction of replication, which changes the repeat sequence that serves as the lagging-strand template (origin switching), or by shifting the location of the origin of replication without altering the replication direction (origin shifting). We propose that changes in the dynamics of replication-fork progression, or architecture, will alter the location of the repeat within the single-stranded lagging-strand template, thereby influencing instability (fork shifting). The fork-shift model, which does not require origin relocation, is influenced by cis-elements and trans-factors associated with driving and maintaining replication forks. The fork-shift model can explain some of the complex behaviours of repeat instability because it is dynamic and responsive to variations in epigenomic and locus activity.

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DNA Polymerase IIIDNA PrimersDNA ReplicationGenomic InstabilityHumansModels, GeneticMutationTrinucleotide Repeat ExpansionJournal ArticleResearch Support, Non-U.S. Gov'tReview

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John D Cleary, Christopher E Pearson. 2005. Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability.. https://doi.org/10.1016/j.tig.2005.03.008

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