The possible roles of human Alu elements in aging

The huge amount of knowledge about the organization and functions of genome structural units accumulated through genome research allows us to examine cell aging processes in detail and to test existing hypotheses of aging. One of the hypothesis currently of interest is that instability of the cell genome is one of the main causes of aging (Vijg and Suh, 2013). Putative causes of genome instability during aging include breakage of double-stranded DNA, telomere shortening, activation of mobile elements, and decreased efficiency of repair systems (Chen et al., 2007; Aubert and Lansdorp, 2008; Maxwell et al., 2011). It is suggested that genome instability of somatic cells has an impact on gene expression and results in disturbance of cell processes, cessation of cellular growth, degeneration and atrophy of cells and tissues as well as aging of the whole organism. The role of mobile elements, in particular Alu retrotransposons, in genome instability and aging deserves special attention. Important questions include whether Alu elements in the human genome are an endogenous source of DNA damage and genome instability and whether they can promote aging of an organism and make a significant contribution to lifespan variation. Alu elements are characterized by considerable polymorphism in human populations. We asked, therefore, whether polymorphism of Alu elements can influence the human lifespan. Opinions about mobile genetic elements have changed radically over the last two decades. Originally, they were characterized as selfish DNA but today we recognize their role in the organization of a genome and the regulation of gene expression (Deininger, 2011). Alu elements are classified as short interspersed elements (SINEs). The human genome contains about ∼106 copies of Alu retrotransposons and they represent ∼10.6% of nuclear DNA. The distributions of different Alu elements within a one chromosome and between different chromosomes are uneven but are not random. Alu elements in human chromosomes 14, 16, and 21 are concentrated in centromeric areas, but clusters of Alu elements are not found in chromosomes 4, 19, 20, X or Y. The distribution of Alu elements is correlated positively with the presence of GpC-containing genome sequences and the distribution of proteincoding genes. These repeating elements are clustered near the genes controlling metabolic, transport, and signaling processes (Grover et al., 2003). Genome instability has been found for all sites containing Alu elements, which serve as “substrates” for homologous recombination owing to their high frequency of occurrence in the eukaryotic genome and the identity of their sequences. Deletions and duplications can appear as the result of crossing-over between similarly oriented elements; e.g., between inversions of opposite orientation (Kolomietz et al., 2002). The existence of an inserted Alu element (AluY) is a predictor of increased recombination variability within 2 kb of the Alu element (Witherspoon et al., 2009). As a result of the analysis of human DNA sequences adjoining the site of recombination, the 26 nt sequence of an Alu element was found within the site or at a distance of 20–50 bp from it. This sequence is similar to that of a χ site, which stimulates recombination in Escherichia coli. Further, a sequence with homology to a translysine-binding site was detected within the Alu element. This protein is involved in partial untwisting of the DNA helix and its linkage with DNA results in increased sensitivity to the action of nucleases and greater probability of recombination (Martinelli et al., 2000). Thus, a large number of Alu elements in the genome and the existence of protein-binding sites in sequences involved in recombination lead to their functioning as potential sites for recombination and, perhaps, promotion of this process. Alu elements are 7SL RNA-like SINEs (Deininger, 2011). Owing to structural features and various functions, Alu elements can participate in the regulation of gene expression and likely influence the expression of many genes by insertion into or close by gene promoter regions. Alu elements contain binding sites for nuclear hormone receptor complexes and a large number of functionally active transcription factors (Polak and Domany, 2006; Deininger, 2011). These sites can compete for linkage of transcription factors with gene promoters or act as promoters for nearby genes. For example, ∼90% of sites responsible for the linkage of retinoic acid are located in Alu elements (Laperriere et al., 2007). Human aging is characterized by dysregulation of alternative splicing (Harries et al., 2011) and Alu elements can interfere with the mechanism underlying gene splicing. The presence of Alu elements in non-translation sites of a gene can result in alternative or aberrant splice sites. About 5% of all human alternative exons contain Alu sequences (Sorek et al., 2002). One of the consequences of the insertion of Alu elements into proteincoding sequences is the occurrence of an additional stop codon and a premature stop of translation resulting in the development of different diseases (Hancks and Kazazian, 2012). For example, the insertion of an Alu element into intron 18 of the human factor VIII gene leads to the absence of exon 19 during the splicing