Translocation and gross deletion breakpoints in human inherited disease and cancer II: Potential involvement of repetitive sequence elements in secondary structure formation between DNA ends

Abstract

Translocations and gross deletions are responsible for a significant proportion of both cancer and inherited disease. Although such gene rearrangements are nonuniformly distributed in the human genome, the underlying mutational mechanisms remain unclear. We have studied the potential involvement of various types of repetitive sequence elements in the formation of secondary structure intermediates between the single-stranded DNA ends that recombine during rearrangements. Complexity analysis was used to assess the potential of these ends to form secondary structures, the maximum decrease in complexity consequent to a gross rearrangement being used as an indicator of the type of repeat and the specific DNA ends involved. A total of 175 pairs of deletion/translocation breakpoint junction sequences available from the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] were analyzed. Potential secondary structure was noted between the 5' flanking sequence of the first breakpoint and the 3' flanking sequence of the second breakpoint in 49% of rearrangements and between the 5' flanking sequence of the second breakpoint and the 3' flanking sequence of the first breakpoint in 36% of rearrangements. Inverted repeats, inversions of inverted repeats, and symmetric elements were found in association with gross rearrangements at approximately the same frequency. However, inverted repeats and inversions of inverted repeats accounted for the vast majority (83%) of deletions plus small insertions, symmetric elements for one-half of all antigen receptor-mediated translocations, while direct repeats appear only to be involved in mediating simple deletions. These findings extend our understanding of illegitimate recombination by highlighting the importance of secondary structure formation between single-stranded DNA ends at breakpoint junctions.

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

“…This confirms previous analysis of translocation breakpoints of which some have shown both GC-rich regions and polypyrimidine and polypurine tracts. 20,21 From our findings we suggest that the sequence similarities (80%) between the two chromosomes flanking the breakpoints as well as the surrounding polypurine and polypyrimidine tracts are predisposing factors for the reciprocal translocation. Recombination-associated sequence motifs have been shown to be over-represented at translocation breakpoints, including DNA polymerase core elements (frameshift hotspots) and heptamer recombination signals.…”

Mutator Phenotype ofCaenorhabditis elegansDNA Damage Checkpoint Mutants

“…Stalled replication forks have been shown to result in DSB formation in Escherichia coli (Michel et al 1997), which may lead to exonucleasemediated DSB resection and end-joining if checkpointmediated homologous recombination fails to resolve the lesion (Moore and Haber 1996;Yu and Gabriel 2003;Guirouilh-Barbat et al 2004). Note that polypurine tracts and direct or inverted repeats have been observed at genome rearrangement breakpoints in bacteria, yeast, and humans Chuzhanova et al 2003;Bacolla et al 2004). The biological relevance of such structures in vivo is emphasized by the two unc-58 deletions with breakpoints at or near a stem loop at the 39-end of a Helitron transposable element.…”

Distinct patterns of germ-line deletions inMLH1 andMSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC)

“…From a mechanistic perspective, the 26 bp "Alu core" is often present closely to the sites of recombination and several motifs located in this sequence are proposed to be recombinogenic, including the pentanucleotide "CCAGC" derived from the chi sequence and translin binding sites (Kanaar et al, 1998;Chuzhanova et al, 2003). However, high Alu density does not always correlate with high degree of susceptibility to genomic rearrangement.…”

“…Thus, the repetitive sequences affect the recombination event at two levels: first, they modulate the local organization of the chromatin therefore contributing to the susceptibility (Kanaar et al, 1998;Chuzhanova et al, 2003). Secondly, they shape the deletion pattern by serving as a favourable substrate for the observed recombinations (Gebow et al, 1999).…”