Dataset Information

The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats.

ABSTRACT: We have demonstrated that the breakpoints of the constitutional t(11;22) are located at palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11. As a mechanism for this recurrent translocation, we proposed that the PATRR forms a cruciform structure that induces the genomic instability leading to the rearrangement. A patient with neurofibromatosis type 1 (NF1) had previously been found to have a constitutional t(17;22) disrupting the NF1 gene on 17q11. We have localized the breakpoint on 22q11 within the 22q11-specific low-copy repeat where the breakpoints of the constitutional t(11;22)s reside, implying a similar palindrome-mediated mechanism for generation of the t(17;22). The NF1 gene contains a 195-bp PATRR within intron 31. We have isolated the junction fragments from both the der(17) and the der(22). The breakpoint on 17q11 is close to the center of the PATRR. A published breakpoint of an additional NF1-afflicted patient with a constitutional t(17;22) is also located close to the center of the same PATRR. Our data lend additional support to the hypothesis that PATRR-mediated genomic instability can lead to a variety of translocations.

SUBMITTER: Kurahashi H

PROVIDER: S-EPMC1180249 | biostudies-literature | 2003 Mar

REPOSITORIES: biostudies-literature

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The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats.

Kurahashi Hiroki H Shaikh Tamim T Takata Masayuki M Toda Tatsushi T Emanuel Beverly S BS

American journal of human genetics 20030129 3

We have demonstrated that the breakpoints of the constitutional t(11;22) are located at palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11. As a mechanism for this recurrent translocation, we proposed that the PATRR forms a cruciform structure that induces the genomic instability leading to the rearrangement. A patient with neurofibromatosis type 1 (NF1) had previously been found to have a constitutional t(17;22) disrupting the NF1 gene on 17q11. We have localized the breakpoint on 22q11 wi ...[more]

PMID: 12557125

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Project description:The constitutional t(11;22) translocation is the only known recurrent non-Robertsonian translocation in humans. Offspring are susceptible to der(22) syndrome, a severe congenital anomaly disorder caused by 3&rcolon;1 meiotic nondisjunction events. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat termed "LCR22" and within an AT-rich repeat on 11q23. The LCR22s are implicated in mediating different rearrangements on 22q11, leading to velocardiofacial syndrome/DiGeorge syndrome and cat-eye syndrome by homologous recombination mechanisms. The LCR22s contain AT-rich repetitive sequences, suggesting that such repeats may mediate the t(11;22) translocation. To determine the molecular basis of the translocation, we cloned and sequenced the t(11;22) breakpoint in the derivative 11 and 22 chromosomes in 13 unrelated carriers, including two de novo cases and der(22) syndrome offspring. We found that, in all cases examined, the reciprocal exchange occurred between similar AT-rich repeats on both chromosomes 11q23 and 22q11. To understand the mechanism, we examined the sequence of the breakpoint intervals in the derivative chromosomes and compared this with the deduced normal chromosomal sequence. A palindromic AT-rich sequence with a near-perfect hairpin could form, by intrastrand base-pairing, on the parental chromosomes. The sequence of the breakpoint junction in both derivatives indicates that the exchange events occurred at the center of symmetry of the palindromes, and this resulted in small, overlapping staggered deletions in this region among the different carriers. On the basis of previous studies performed in diverse organisms, we hypothesize that double-strand breaks may occur in the center of the palindrome, the tip of the putative hairpin, leading to illegitimate recombination events between similar AT-rich sequences on chromosomes 11 and 22, resulting in deletions and loss of the palindrome, which then could stabilize the DNA structure.

Project description:BackgroundREPs (Repetitive Extragenic Palindromes) are small (20-40 bp) palindromic repeats found in high copies in some prokaryotic genomes, hypothesized to play a role in DNA supercoiling, transcription termination, mRNA stabilization.ResultsWe have monitored a large number of REP elements in prokaryotic genomes, and found that most can be sorted into two large DNA super-families, as they feature at one end unpaired motifs fitting either the GTAG or the CGTC consensus. Tagged REPs have been identified in >80 species in 8 different phyla. GTAG and CGTC repeats reside predominantly in microorganisms of the gamma and alpha division of Proteobacteria, respectively. However, the identification of members of both super- families in deeper branching phyla such Cyanobacteria and Planctomycetes supports the notion that REPs are old components of the bacterial chromosome. On the basis of sequence content and overall structure, GTAG and CGTC repeats have been assigned to 24 and 4 families, respectively. Of these, some are species-specific, others reside in multiple species, and several organisms contain different REP types. In many families, most units are close to each other in opposite orientation, and may potentially fold into larger secondary structures. In different REP-rich genomes the repeats are predominantly located between unidirectionally and convergently transcribed ORFs. REPs are predominantly located downstream from coding regions, and many are plausibly transcribed and function as RNA elements. REPs located inside genes have been identified in several species. Many lie within replication and global genome repair genes. It has been hypothesized that GTAG REPs are miniature transposons mobilized by specific transposases known as RAYTs (REP associated tyrosine transposases). RAYT genes are flanked either by GTAG repeats or by long terminal inverted repeats (TIRs) unrelated to GTAG repeats. Moderately abundant families of TIRs have been identified in multiple species.ConclusionsCGTC REPs apparently lack a dedicated transposase. Future work will clarify whether these elements may be mobilized by RAYTs or other transposases, and assess if de-novo formation of either GTAG or CGTC repeats type still occurs.

Dataset Information

The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats.

Publications

The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats.

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