The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors

Abstract

There is increasing evidence for the involvement of repetitive DNA sequences as facilitators of some of the recurrent chromosomal rearrangements observed in human tumors. The high densities of repetitive DNA, such as Alu elements, at some chromosomal translocation breakpoint regions has led to the suggestion that these sequences could provide hot spots for homologous recombination, and could mediate the translocation process and elevate the likelihood of other types of chromosomal rearrangements taking place. The Alu core sequence itself has been suggested to promote DNA strand exchange and genomic rearrangement, and it has striking sequence similarity to (which has been shown to stimulate recBCD-mediated recombination in Escherichia coli). Alu repeats have been shown to be involved in the generation of many constitutional gene mutations in meiotic cells, attributed to unequal homologous recombination and consequent deletions and/or duplication events. It has recently been demonstrated that similar deletion events can take place in neoplasia because several types of leukemia-associated chromosomal rearrangements frequently have submicroscopic deletions immediately adjacent to the translocation breakpoint regions. Significantly, these types of deletions appear to be more likely to take place when the regions subject to rearrangement contain a high density of Alu repeats. With the completion of the Human Genome Project, it will soon be possible to create more comprehensive maps of the distribution and densities of repetitive sequences, such as Alu, throughout the genome. Such maps will offer unique insights into the relative distribution of cancer translocation breakpoints and the localization of clusters of repetitive DNA.

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

“…A correlation study of Alu density and breakpoint cluster on chromosome 22 demonstrated that cancer-related breakpoints are exclusively mapped to regions with Alu density higher than 20%. At the same time, regions of high Alu density without known breakpoints are also present (Kolomietz et al, 2002). Regions of high Alu density with low rearrangement frequency are also observed in our analysis, such as intron 5 in MSH2 and intron 15 in MLH1 (Fig.…”

“…Our study of germ-line mutations among HNPCC patients suggests an important contributory role for Alu sequences in the type and frequency of genomic rearrangements. For both loci of MLH1 and MSH2, the average Alu density at the intronic regions are above 20%, which is often observed at cancer-related regions (Kolomietz et al, 2002). Among the introns, the highest density of breakpoints is co-localized with the highest Alu density; intron 6 of MLH1 and intron 2 of MSH2, respectively (Fig.…”

“…However, these possibly biased samples can still provide important clues for understanding the mechanism underlying recombination events. Although Alu has been reported to be the underlying basis of DNA breakpoints in many types of inherited diseases (Deininger and Batzer, 1999;Kolomietz et al, 2002), it remains to be answered if this type of element drives the genomic rearrangement or has just been involved passively. Our study of germ-line mutations among HNPCC patients suggests an important contributory role for Alu sequences in the type and frequency of genomic rearrangements.…”

Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients

“…The involvement of Alu elements in recombination is reported as one of the causes of human genetic diseases, including tumors. 30,31 Although the precise structure of this region is still unknown, a possible mechanism of the large deletion and inversion is illustrated in Figure 3c. Application of a high-density SNP mapping microarray analysis enables us to detect deletions and amplifications at a genome-wide level.…”

Useful ‘junk’: Alu RNAs in the human transcriptome

“…Whereas the results discussed here focus on the beneficial effects of Alu element insertion, the same process could also be detrimental for the organism. By inserting into essential genes, Alu elements can indeed annihilate important physiological functions; moreover, because of their high level of sequence homology, they can also mediate important disease-causing genomic rearrangements [76]. The duality of the effect of Alu element insertion demonstrates that Alu amplification has not been a neutral process; on the contrary, that it has been actively participating in genome evolution.…”