Abstract 5150: What is in control of DNA replication timing.

Abstract

Abstract The initiation of DNA replication at specific sites in the genome is known to be far from perfect, where known initiation sites may or may not fire in a given single cell during specific cell cycle. At the same time, from larger scale perspective, one finds that the timing of DNA replication is highly orchestrated, where specific regions in the genome are copied at specific, reproducible time points throughout S-phase. In an attempt to reconcile these two somewhat discordant observations, many researchers have assumed that a yet unknown, active regulatory mechanism in the cell is responsible for coordinating replication timing. Here we present a mechanistic explanation for genome-wide replication timing patterns. Our model is purely stochastic, does not contain any active control components and reproduces existing replication timing data with extreme fidelity (correlation > 0.9, about the same as the correlation between technical replicates of the experiment). The main findings of our work are • Existence of reproducible genome-wide replication patterns do not logically necessitate existence of a complex, active control system in the cell • Integrative analysis of recently released ENCODE data identifies semi-local chromatin structure as the main determinant of replication timing • Plasticity of replication timing across different cell types are a direct consequence of changes in the chromatin structure between the different cell differentiation states • Replication timing is a “systems” phenomenon emerging from the collective action of many uncoordinated, stochastic replication initiation sites. Replication timing cannot be understood by investigating individual initiation sites: deleting up to 30% of high probability initiation sites does not significantly change replication timing Citation Format: Yevgeniy Gindin, Paul S. Meltzer, Sven Bilke. What is in control of DNA replication timing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5150. doi:10.1158/1538-7445.AM2013-5150