Replication Timing Dictates the Frequency of Chromosomal Translocations

Chromosomal translocations are common in cancer, resulting in oncogenic fusions or aberrant expression by bringing proto-oncogenes closer to enhancers or promoters. For example, during antibody maturation within B cells, activation-induced deaminase (AID) generates mutations that can lead to double-strand breaks (DSB) in the immunoglobulin (Ig) genes, and the subsequent ligation of these DSBs can generate a characteristic translocation between Ig genes and oncogenes such as MYC. To investigate mechanisms that link DSB formation to the ligation of partner loci, Peycheva and colleagues studied the paradigmatic Myc–immunoglobulin heavy chain (Igh) translocation in a murine B lymphoma cell line. Knockdown of Mcm6, a replicative helicase that licenses origins of replication during the S phase of the cell cycle, reduced origin activation frequencies while decreasing Myc–Igh translocations. Indeed, AID-dependent translocation hotspots significantly overlapped with replication initiation sites, suggesting that the activity of replication origins may influence translocation biogenesis. To test whether translocation frequency could be impacted by replication timing (RT), which is influenced by activity of origins of replication, the promoter-proximal origin at Myc was deleted (Myc^ΔORI), decreasing the rate of AID-dependent Myc translocations genome-wide. Mcm6 knockdown also globally dysregulated RT and was accompanied by decreased AID-dependent Myc translocations. Moreover, in Myc^ΔORI cells, restoration of origin activity through knockin of the Myc origin downstream of the Myc^ΔORI allele rescued the Myc–Igh translocation frequency, demonstrating that early RT was critical for AID-dependent translocation. Importantly, this RT-dependent mechanism was found to function downstream of DSB formation and independently of DSB frequency. Chromosome conformation capture analysis revealed that origin activity at Myc was required for nuclear proximity between Myc and Igh, supporting that shared early RT might underlie translocation between partner loci by increasing the frequency of physical contact. Similarly, disruption of synchronized early RT also affected translocation frequency of other well-established translocations, including AF4–MLL1 and BCL6–IGH. In summary, the results of this study reveal a mechanism by which oncogenic chromosomal translocations are directly influenced by DNA replication timing.

Peycheva M, Neumann T, Malzl D, Nazarova M, Schoeberl UE, and Pavri R. DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations. Science 2022;377:eabj5502.

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