DNA replication in humans requires precise regulation to ensure accurate genome duplication and maintain genome integrity.
A key indicator of this regulation is replication timing, which reflects the interplay between origin firing and fork dynamics.
We present a high-resolution (1-kilobase) mathematical model that maps firing rate distributions to replication timing profiles across various cell lines, validated using Repliseq data.
The model effectively captures genome-wide replication patterns while identifying local discrepancies. Notably, regions where the model and data diverge often overlap with fragile sites and significant genes, highlighting the influence of genomic architecture on replication dynamics.
Conversely, areas of high concordance are associated with open chromatin and active promoters, where elevated firing rates facilitate timely fork progression and reduce replication stress. By establishing these correlations, our model provides a valuable framework for exploring the structural interplay between replication timing, transcription, and chromatin organisation.
It offers new insights into the mechanisms underlying replication stress and its implications for genome stability and disease.
Read the pre-print here: https://www.biorxiv.org/content/10.1101/2024.11.25.625090v1
Francisco Berkemeier
Francisco is a mathematician specialising in modelling the complex dynamics of DNA replication in human cells. His research explores how coordinating origin firing and fork progression influences replication timing. By developing detailed kinetic models, he aims to uncover how disruptions in this coordination lead to replication stress, a precursor to genomic instability and cancer. His work helps provide essential insights into the cellular mechanisms driving disease.
Francisco is a member of Professor Michael Boemo's Lab.