Figure 1. Fragile Zones in Human Lymphoid Chromosomal Translocations.

Schematics of the BCL2 break cluster regions on chromosome 18, the BCL1 breakpoint region (which is downstream of the cyclin D1 (CCND1) gene) on chromosome 11, Exon 13 of E2A (also known as TCF3) on chromosome 19, and the CRLF2 breakpoint region upstream of the CRLF2 gene on the X chromosome illustrate the accumulation of breakpoints within the various regions. Breakpoint junctions sequenced from human patients demonstrate that DSBs anywhere within these regions can result in chromosomal translocations relevant for various B cell malignancies (red vertical lines represent a mapped breakpoint), within these regions, however, are regions where breakpoints appear to cluster in a non-random fashion (red starbursts). In the BCL2 region (top), relative proportions of breakpoints at the BCL2 major breakpoint region (MBR), intermediate cluster region (ICR), and minor cluster region (MCR) are shown. The MBR is located in the third exon of the BCL2 gene within the 3′ untranslated region (UTR), while the ICR and MCR are further downstream from the translated region. The 175 bp MBR, 105 bp ICR, and 561 bp MCR account for about 50%, 13%, and 5% of the BCL2 translocation breakpoints. Within the BCL1 region, the major translocation cluster (MTC) is located about 110 kb from the CCND1 gene. The 150 bp MTC contains about 30% of breakpoints, whereas the remaining 70% of events are distributed widely over the surrounding 340 kb as recently mapped and sequenced [33]. In the E2A cluster, which occurs in intron 13 of the E2A gene [34], 75% of breakpoints occur in the 23 bp E2A cluster, while the surrounding 3 kb only account for 25%. The CRLF2 cluster lies upstream of the CRLF2 gene with 32% of mapped break in the 25 kb region occurring within a 311 bp cluster. These sites of breakpoint accumulation that range from 23 to 561 bp are termed ‘fragile zones’ and every CG sequence motif in each of these fragile zones is a hotspot for human translocation [2, 33].