The Possible Roles of Human Alu Elements in Aging

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provided by Frontiers - Publisher Connector OPINION ARTICLE published: 28 May 2013 doi: 10.3389/fgene.2013.00096 The possible roles of human Alu elements in aging

O. E. Mustaﬁna*

Institute of Biochemistry and Genetics, Ufa Research Center, Russian Academy of Sciences, Ufa, Russia *Correspondence: [email protected] Edited by: Elena G. Pasyukova, Institute of Molecular Genetics of Russian Academy of Sciences, Russia Reviewed by: Elena G. Pasyukova, Institute of Molecular Genetics of Russian Academy of Sciences, Russia Joan Fibla, University of Lleida, Spain

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

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process, which results in development of Alu elements and their methylation is a In conclusion, Alu elements, which thesevereformofhemophilia(Ganguly primary mechanism of transposon activ- are components of the complex net- et al., 2003). Alu elements can act as anti- ity suppression (Schmid, 1991; Slotkin and work of interrelated molecular and genetic sense regulators of transcription. Alu ele- Martienssen, 2007). It is supposed that changes; can have a role in structural and ments in gene introns might be located changes in the methylation status of Alu functional damage of the human genome in anti-sense orientation regarding the elements can act as global modifiers of during aging. Activation of Alu elements direction of gene transcription; therefore, gene expression and it is worth noting the in response to environmental factors could anti-sense RNA complementary to mRNA inter-individual variability of the methy- be one of the triggers that mediate genome can be synthesized, and this is able to lation profile of Alu elements; indeed, instability, alter the expression levels of suppress splicing and mRNA translation. their epigenetic changes throughout life genes, and lead to the gradual diminution Anti-sense interactions of Alu transcripts have been observed in monozygotic twins of cell functions and organism functional- with mRNA likely have a major role in the (Fraga et al., 2005; Sandovici et al., 2005). ity as a whole. regulation of translation, degradation of It was suggested that demethylation of Alu mRNA, and change of gene transcription elements makes a significant contribution ACKNOWLEDGMENTS (Häsler and Strub, 2006). The insertion of to global hypomethylation of the genome The author was supported by grants Alu elements into genes creates alternative in aging (Bollati et al., 2009; Jintaridth and from the Russian Foundation for Basic sites of polyadenylation, which is one of Mutirangura, 2010; Gentilini et al., 2012). Research. the important stages of mRNA maturation Some research data reveal regulatory inter- before translation. The human genome actions between Alu elements and microR- REFERENCES contains ∼10,000 Alu elements located in NAs (miRNAs) (Smalheiser and Torvik, Athanasiadis, A., Rich, A., and Maas, S. (2004). the 3-untranslated region of coding genes, 2006; Lehnert et al., 2009). The Alu ele- Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. and 1% of them are active as polyadeny- ments localized in 3 -untranslated regions 2:e391. doi: 10.1371/journal.pbio.0020391 lation sites (Chen et al., 2009). 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