Which gene sequences are actively read by transcription machinery in the cell nucleus to produce RNA (some of which is then translated into proteins) is determined by the structure of nuclear DNA. The various assemblies of proteins making up that transcription machinery will read whatever sequence they can attach to. Regions of nuclear DNA can be packaged away and tightly furled, made inaccessible, or otherwise become accessible for a time through alterations to histone proteins, methylation of specific sites on the genome, and other strategies. All of this changes constantly in response to circumstances, many dynamic feedback loops of RNA and protein production and structural change to DNA all interacting with one another.
In today's open access paper, researchers offer a view of DNA structure that is less commonly discussed in the context of aging and longevity. This view emerges from the use of spectroscopy, which can be employed to gain insight into different structural variants of DNA. The double helix structure familiar to laypeople is known as B-DNA, but A-DNA and Z-DNA also exist. Spectroscopy can further can be used to visualize a range of small-scale features in the chemical structure of DNA, such as sugar puckers. Evidently, however one looks at DNA and gene expression, one is going to see differences between short-lived rodents and long-lived rodents.
What can be done with this information? At present very little. As is the case for epigenetic measures, there is no bridge of cause and consequence yet built to link specific structural DNA changes and specific forms of damage and dysfunction in aging. So one can measure structural differences across life spans within species and between species of different life spans, but it doesn't yet much help in the matter of how to build effective rejuvenation therapies.
The structural architecture of DNA, extending beyond its sequence-dependent genetic code, has emerged as a critical determinant of genomic stability, cellular function, and organismal longevity. B-DNA, which has a right-handed double helix structure with Watson-Crick base pairing, can form non-B DNA structures such as hairpins, triplexes, cruciform, left-handed Z-forms, G-quadruplexes, and A-motifs under specific conditions. While canonical B-form DNA represents the classical double-helical structure, dynamic conformational shifts, such as transitions to A-DNS or Z-DNA alter biochemical properties like flexibility, stability, and protein interactions, with profound implications for aging and disease.
Structural changes, such as the transition from B-DNA to A-DNA, influence DNA stability and flexibility and are affected by factors like DNA methylation and sugar puckering. This study is the first to investigate the relationship between DNA conformational changes and lifespan in two rodent species. The analysis focused on long-lived Anatolian blind mole-rat (Nannospalax xanthodon) and shorter-lived rat (Rattus rattus), utilizing infrared spectroscopy and principal component analysis (PCA) to examine liver DNA.
Results indicated that transitions from B-form to A-form and Z-form were more prevalent in N. xanthodon than in R. rattus. However, the dominant DNA conformations in both species are in B-form. Additionally, N-type sugar puckers (C3-endo conformation), associated with these DNA forms, were more prominent in N. xanthodon. In contrast, S-type sugar puckers (C2-endo conformation), characteristic of B-DNA, were found at lower levels in N. xanthodon. Furthermore, variations in methylation-specific structural modifications of nucleobases were quantitatively assessed among these species.
The study proposes a significant connection between the long lifespan of N. xanthodon, which live underground, and their unique DNA structure, offering insights into how different DNA forms, as well as the conformations of their backbone and sugar-base components, may affect longevity, highlighting potential research avenues regarding the biomolecular aspects of aging.
View the full article at FightAging
