Novel 22q112 Translocations

Chromosome regions harboring breakpoints in cell lines from individuals carrying novel translocations within the 22q11.2 region were mapped to ascertain whether there could share

Fig. 3. AT-rich palindromes mediate the t(11;22) and the t(17;22) translocation. AT-rich palindromes on chromosomes 11q23.3, 17q11.2, and 22q11.7 can form cruciform structures as shown. The regions on chromosomes 11 and 22 form perfect palindromes, whereas the region on chromosome 17 contains non-palindromic sequences in the center of the cruciform structure, depicted as a look. Although the sequences in all three chromosomes are AT-rich, they are not homologous to each other.

Fig. 3. AT-rich palindromes mediate the t(11;22) and the t(17;22) translocation. AT-rich palindromes on chromosomes 11q23.3, 17q11.2, and 22q11.7 can form cruciform structures as shown. The regions on chromosomes 11 and 22 form perfect palindromes, whereas the region on chromosome 17 contains non-palindromic sequences in the center of the cruciform structure, depicted as a look. Although the sequences in all three chromosomes are AT-rich, they are not homologous to each other.

Fig. 4. Model of mechanism for translocations mediated by AT-rich palindromes. Palindromes are prone to double strand breaks which lead to translocations repaired by non-homologous end-joining (NHEJ). Although the sequences in all three chromosomes are AT-rich, they are not homologous to each other. When a breakpoint occurs in the labile loop created at the tips of the cruciform structure, a translocation may occur, resulting in a more stable non-palindromic sequence (43). The arrows depict the orientation of DNA sequence with respect to the centromere. (Modified from refs. 48,49.)

Fig. 4. Model of mechanism for translocations mediated by AT-rich palindromes. Palindromes are prone to double strand breaks which lead to translocations repaired by non-homologous end-joining (NHEJ). Although the sequences in all three chromosomes are AT-rich, they are not homologous to each other. When a breakpoint occurs in the labile loop created at the tips of the cruciform structure, a translocation may occur, resulting in a more stable non-palindromic sequence (43). The arrows depict the orientation of DNA sequence with respect to the centromere. (Modified from refs. 48,49.)

common features. Most breakpoints occurred in the proximal half of chromosome 22q11.2. Of these, half map to the LCR22s. Among the LCR22s, most were in LCR22-3a, the LCR22 associated with the t(11;22) translocation (54). In two reports of translocations disrupting LCR22-3a (LCR22-B), one showed the breakpoint occurred between AT-rich palindromes in LCR22-3a and on the partner chromosome 4q35 (55) but the other did not (chromosome X) (56), implicating different mechanisms. In our study, half of the translocations disrupting 22q11.2 occurred distal to the most telomeric unique sequence probe (54). The breakpoints on the partner chromosomes occurred more frequently in telomeric bands, supporting the epide-

miological data that breakpoints in telomeric bands are more common events than other regions within chromosomes. Previous reports have noted a higher rate of telomeric rearrangements than other chromosomal bands (57). Telomeric regions are very dynamic and have shuffled during evolution between nonhomologous chromosomes (58,59). An ascertainment bias toward imbalance of smaller segments as opposed to larger segments could explain the occurrence of 22q11.2 and telomeric rearrangements, but it is also possible that two susceptible regions misalign and pair following chromosome breakage.

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