Spatial genome organization in the formation of chromosomal translocations

Abstract

Chromosomal translocations and genomic instability are universal hallmarks of tumor cells. While the molecular mechanisms leading to the formation of translocations are rapidly being elucidated, a cell biological understanding of how chromosomes undergo translocations in the context of the cell nucleus in vivo is largely lacking. The recent realization that genomes are non-randomly arranged within the nuclear space has profound consequences for mechanisms of chromosome translocations. We review here the emerging principles of spatial genome organization and discuss the implications of non-random spatial genome organization for the genesis and specificity of cancerous chromosomal translocations.

Figure 1. Formation of chromosomal translocations is a multi-step process

Chromosomal translocations form after double strand breaks (arrows) often inflicted by radiation or genotoxic chemicals. The repair machinery (purple, blue) is recruited to the double strand breaks, but if it fails to repair the damaged chromosome territories (red, green), they undergo illegitimate misjoining to form chimeric chromosomes.

Figure 2. Spatial organization of genomes

The non-random arrangement of chromosomes and genes can be described as (A) radial position relative to the nuclear center or (B) relative position with respect to other chromosomes or genes. (A) The radial position of chromosomes has been correlated with either gene density (top) or chromosome size (bottom). (B) Chromosomes and genes may either be proximally or distally located relative to each other (top) and their position may be constrained by intranuclear structures such as the nucleolus (yellow).

Figure 3. Spatial proximity in the formation of translocations

Increasing evidence suggests a link between relative spatial positioning of chromosomes and their frequency of translocation. Proximally positioned chromosome (red, green) undergo translocations at a higher frequency than distally positioned chromosomes (blue).

Figure 4. “Breakage-first” and “Contact-first” models for formation of chromosome translocations

(top) Breakage-first: Chromosomal translocations may either form by joining of DSBs in distantly located chromosomes. In this model the broken chromosome ends are able to diffuse over large distances to roam the nuclear space for possible translocation partners. (bottom) Contact-first: Translocations may preferentially form between already proximally positioned genome regions in which breaks occur.