Epigenetic instability induced by replication of structured DNA

My talk will focus on the interaction between DNA secondary structures and the replication machinery and how problems handling these structures can lead to changes in the chromatin landscape and altered gene expression. I will discuss the evidence for a model in which replication fork stalling at secondary structures, especially G quadruplexes, leads to localised uncoupling of DNA synthesis from histone recycling and consequently to failure of the faithful propagation of histone modifications through replication. I will focus on our genetic manipulation of G quadruplexes, and other sequences with structure-forming capacity, in a model locus in chicken DT40 cells that allows us to monitor epigenetic stability with great sensitivity. This approach has taught us both about the formation and replication of secondary structures and the mechanisms that propagate chromatin modifications during replication, and has uncovered an important vulnerability in the mechanism of cellular transcriptional memory that may have important implications for development and cancer.