Double-strand breaks in motion: implications for chromosomal rearrangement

Abstract

DNA double-strand breaks (DSBs) must be rejoined properly to prevent the occurrence of serious genomic rearrangements associated with many human diseases. Non-homologous end joining (NHEJ) is a DSB repair mechanism known to protect genomic integrity that is also implicated in creating genomic translocations, inversions, deletions, and insertions. We recently investigated the impact of the pre-damage spatial proximity of DSB-bearing loci on the frequency of trans repair by NHEJ and surprisingly found no correlation between them. In this review, we consider various models that might account for these unexpected results. While DSB movement is necessary to explain our findings, many questions remain about the nature and timing of that motion.

Keywords: DNA repair; Homologous recombination; Movement; Non-homologous end joining; Nucleus.

Fig. 1.. Logic of the system to study trans NHEJ.

Schematics show (A) definitions of cis and trans repair with respect to the pairing of ends between two DSBs, and (B) configuration of the reporter assay used to detect rearrangements in Sunder and Wilson 2019.

Fig. 2.. Simple models of possible DSB movement leading to trans NHEJ.

Colored symbols indicate cut ends from two loci, black lines indicate duplex DNA, stacked dashed lines indicate DSB end tethering, and arrows indicate movement, which might be random (A to C) or directional (D, E). Inter-DSB contact is required for trans NHEJ, which might be transient (C) or stabilized by DSB affinity for a nuclear sub-structure (D) or other DSBs (E).

Fig. 3.. Multi-stage models of possible DSB disposition in NHEJ and HR.

Flow charts (similar to Fig. 2) depict potential steps leading to NHEJ and HR repair of DSBs; see text for detailed discussion.