Shilovsky G.A.1, Shram S.I.2, Khokhlov A.N.1
1Evolutionary Cytogerontology Sector, School of Biology, Moscow State University, Moscow, Russia
2Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia;
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Various harmful genome modifications (mutations, unrepairable DNA damage, etc.) are known to accumulate with age. This leads to impairment of the genome functioning. The accumulation is due both to increased production of reactive oxygen species and reduction in antioxidant defense and DNA repair efficacy. At present, however, an important role in regulating of the genome stability is given also to epigenetic factors. In this regard, posttranslational modifications of chromatin-associated proteins are of special interest for molecular gerontology. The significance of this process is already shown, for example, for histone deacetylation. However, the role of poly(ADP-ribosyl)ation is less clear. This is one of the earliest cell responses to DNA damage catalyzed by a family of transferases – poly(ADP-ribose) polymerases (PARP). The most studied is the principal member of the family – PARP-1 (EC 2.4.2.30). Poly(ADP-ribosyl)ation is accompanied by a number of cellular processes, including DNA repair, replication and recombination, as well as apoptosis and necrosis. To understand PARP role in aging and lifespan determination, the data on changes of PARP activity and PARP-1 gene expression with age and in aging-associated diseases, with special attention given to the use of various molecular-genetic approaches (knockdown, knockout, etc.), are reviewed. Analysis of other researchers' results and our own data demonstrates that PARP activity paradoxically decreases with age while the level of PARP-1 stays the same and the level of the PARP-activating DNA breaks increases. This might serve as a predictor of age-related pathologies and genomic instability, as well as a perspective marker of aging. Changes in the size and number of poly(ADP-ribose) chains as well as in the proportion and pattern of poly(ADP-ribosyl)ated nuclear proteins leading to impairment of their functioning are suggested as the possible reasons for the unusual change of PARP activity mentioned.