Chromosomal Rearrangements and Chromothripsis: The Alternative End Generation Model

Abstract

Chromothripsis defines a genetic phenomenon where up to hundreds of clustered chromosomal rearrangements can arise in a single catastrophic event. The phenomenon is associated with cancer and congenital diseases. Most current models on the origin of chromothripsis suggest that prior to chromatin reshuffling numerous DNA double-strand breaks (DSBs) have to exist, i.e., chromosomal shattering precedes rearrangements. However, the preference of a DNA end to rearrange in a proximal accessible region led us to propose chromothripsis as the reaction product of successive chromatin rearrangements. We previously coined this process Alternative End Generation (AEG), where a single DSB with a repair-blocking end initiates a domino effect of rearrangements. Accordingly, chromothripsis is the end product of this domino reaction taking place in a single catastrophic event.

Keywords: Alternative End Generation (AEG); Alternative End Joining (AEJ); DNA double-strand break repair; chromosomal rearrangements; chromothripsis.

Figure 1

Relation between proximity to a single DSB and rearrangement frequency. Genes in proximity to the primary break site (Myc locus) are highly predisposed to becoming involved in a translocation reaction. Translocation events are gradient-colored (red to black), where intrachromosomal (red) are distinguished from interchromosomal (black) translocations. The number of genes with a defined number of rearrangements are grouped and plotted against the number of rearrangements. A small group of genes (e.g., Pim1, IL4ra, and Cd83) are interchromosomal but in fact reside proximal to the DSB. (Adapted from Hogenbirk, M. A. et al. PNAS 2016).

Figure 2

Modeling Chromothripsis: Shattering versus Consecutive Rearrangements. Schematic overview of consecutive AEG reactions leading to multiple different types of rearrangements and the comparison with a shattering-based model. In the shattering model, numerous DSBs are required to enable chromothripsis. In contrast, the AEG model proposes that a single DSB—here, between region e and f—generates a repair-blocking passive end (P) and an intact, i.e., active (A), DNA end. Because the P end blocks DSB repair, the A end is recombined preferentially with proximal accessible elements. This process, which can be associated with deletions, insertions, inversions, and double-minute formation, generates an alternative active end sustaining the domino effect. This catastrophic recombination process stops when the P end is resolved or deleted. While both chromosomal shattering and AEG result in the same chromothripsis product, this viewpoint likes to consider AEG as a model for chromothripsis.