Replication Stress, Genomic Instability, and Replication Timing: A Complex Relationship

Abstract

The replication-timing program constitutes a key element of the organization and coordination of numerous nuclear processes in eukaryotes. This program is established at a crucial moment in the cell cycle and occurs simultaneously with the organization of the genome, thus indicating the vital significance of this process. With recent technological achievements of high-throughput approaches, a very strong link has been confirmed between replication timing, transcriptional activity, the epigenetic and mutational landscape, and the 3D organization of the genome. There is also a clear relationship between replication stress, replication timing, and genomic instability, but the extent to which they are mutually linked to each other is unclear. Recent evidence has shown that replication timing is affected in cancer cells, although the cause and consequence of this effect remain unknown. However, in-depth studies remain to be performed to characterize the molecular mechanisms of replication-timing regulation and clearly identify different cis- and trans-acting factors. The results of these studies will potentially facilitate the discovery of new therapeutic pathways, particularly for personalized medicine, or new biomarkers. This review focuses on the complex relationship between replication timing, replication stress, and genomic instability.

Replicative Instability Drives Cancer Progression

“…Strikingly, we found that the number of gene-level gains and heterozygous losses dwarfed that observed for amplifications, homozygous deletions, or mutations. Additionally, copy number trends associated with replication timing did not correlate with our findings (28); MYBL2 High tumors acquired similar numbers of gains and heterozygous losses across both ERFS and MiDAS loci, with a trend toward more heterozygous losses ( Figure 4C ). This data is consistent with previous findings where elevated MMEJ activity is coincident with increased loss of heterozygosity events (29).…”

“…These circumstances make MiDAS genes difficult to replicate and cells frequently commit to mitosis prior to completing replication at these sites. Late replicating genomic regions have been associated with increased deletions as cells use various methods to complete replication (28). Given this, we hypothesized that MYBL2 High tumors acquire greater numbers of genomic alterations at replication stress sensitive (RSS) sites.…”

RIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair

“…The availability of initiation factors naturally limits the number of origins that may be fired early and selects the remaining origins to be fired late [ 63 ]. Alterations in replication timing are mutually dependent on the structure of the genome, including its sequence and epigenetic pattern (reviewed in [ 64 ]). RIF1 prevents middle/late origin firing by mechanisms that are presented in subsequent sections [ 13 ].…”

“…Genomic instability supports the fast accumulation of genetic and epigenetic changes fueling cancer transformation, and otherwise impairs normal cellular functioning [ 78 ]. Replication stress, a phenomenon causing stalling, breakage, or collapse of replication fork, affects RT (reviewed in [ 64 , 79 ]). Replication stress is targeted by DDR, the main collective mechanism to maintain genomic stability [ 80 ].…”

A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

“…RT is triggered at certain point during cell cycle and its development is synchronized with changes in genome organization. RT is connected to processes like 3D genome organization, transcription, epigenetic modulation and mutation, and spatial distribution, and is thought to influence replicative stress and consequently genomic stability (Briu et al 2021).…”