Fig. 7
Late replication timing is more sensitive to genetic and epigenetic damage. Replication timing is spatially organised within the nucleus. Transcriptionally active early-replicating loci are often close in proximity with each other in transcriptional hubs towards the nuclear centre51,78,79. Transcriptionally inactive late-replicating loci are typically heterochromatin, condensed and localised to the nuclear periphery and nuclear lamina51,78,79. In prostate and breast cancer cells, early-replicating loci remain transcriptionally active, however, late-replicating loci switch from a methylated H3K9me3-marked constitutive heterochromatin state to a hypomethylated H3K27me3-marked facultative heterochromatin state, and potentially more susceptible to DNA damage and/or error-prone repair leading to an increase in chromosomal rearrangements. We speculate that if a DNA break occurs in late replication it is more likely to be repaired in cis as late-replicating loci are more self-contained and located towards the nuclear periphery. In contrast, if a break occurs in early replication, this is more likely to result in trans translocations, as there is increased potential for interchromosomal interactions within structures like transcriptional hubs in the nuclear centre
