The cellular etiology of chromosome translocations

Abstract

Chromosome translocations are the most severe form of genome defect. Translocations represent the end product of a series of cellular mistakes and they form after cells suffer multiple DNA double strand breaks (DSBs), which evade the surveillance mechanisms that usually eliminate them. Rather than being accurately repaired, translocating DSBs are misjoined to form aberrant fusion chromosomes. Although translocations have been extensively characterized using cytological methods and their pathological relevance in cancer and numerous other diseases is well established, how translocations form in the context of the intact cell nucleus is poorly understood. A combination of imaging approaches and biochemical methods to probe genome architecture and chromatin structure suggest that the spatial organization of the genome and features of chromatin, including sequence properties, higher order chromatin structure and histone modifications, are key determinants of translocation formation.

Figure 1. The presence of breaks and the spatial arrangement of chromosomes influence translocation frequency

Translocations cannot form in the absence of breaks. In the presence of breaks, the spatial positioning of the broken chromosomes affects translocation outcome. Proximal breaks translocate with high frequency. Distal breaks can also translocate, albeit at lower frequency.

Figure 2. DNA and chromatin features in breakage susceptibility

DNA sequence features (green), histone modifications (yellow), and chromatin structure (red) may facilitate breakage susceptibility and represent an important upstream event in translocation formation. (right) The combined effect of sequence and chromatin features is evident in prostate cancer, where liganded androgen receptor (AR) recruits AID and TOP2B to translocation breakage sites.