Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability.
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.
Cleary
John D
JD
Department of Molecular and Medical Genetics, University of Toronto, The Hospital for Sick Children, Ontario, Canada M5G 1X8.
Pearson
Christopher E
CE
D004258:DNA Polymerase III / Q000502:physiology; D017931:DNA Primers; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D017931:DNA Primers; D004258:DNA Polymerase III