Epigenetic vs. Sequence-dependent control of eukaryotic replication timing

Abstract

Eukaryotic DNA replication follows a reproducible temporal pattern throughout S phase known as the replication timing (RT) program. RT is correlated with gene expression, chromatin structure, and 3D chromatin folding states; it helps to maintain genome integrity, correlates with mutation frequencies, and is altered in many diseases. However, the mechanisms regulating RT remain poorly defined. Studies over the last three decades have attempted to identify specific DNA sequences that regulate this program from yeasts to humans. Recent studies have implicated defined protein-binding motifs in yeasts. In mammals, there is indisputable evidence that epigenetic mechanisms regulate homologue-specific differences in RT, while artificial constructs have been shown to influence RT in a sequence-dependent manner and genomics approaches find compelling correlations of sequence variation to RT. However, the mechanisms linking these features to RT remain elusive.