DNA Gaps as a Protective Mechanism that Limits DNA Damage
This fascinating paper discusses the phenomenon of DNA gaps, essentially a double strand break in which the break is hidden from the usual mechanisms that respond to and repair such damage. The authors present evidence for these DNA gaps to be protective against DNA damage, noting that a loss of DNA gaps is associated with degenerative aging in animal models, both induced aging and natural aging. It is a little early to speculate on what can be done with this information, but it is interesting to join the dots with other research into DNA damage conducted in recent years.
The endogenous DNA damage triggering an aging progression in the elderly is prevented in youth, probably by naturally occurring DNA gaps. Decreased DNA gaps are found during chronological aging in yeast. So we named the gaps "Youth-DNA-GAPs." The gaps are hidden by histone deacetylation to prevent DNA break response and were also reduced in cells lacking either the high-mobility group box (HMGB) or the NAD-dependent histone deacetylase, SIR2. A reduction in DNA gaps results in shearing DNA strands and decreasing cell viability. The number of Youth-DNA-GAPs were low in senescent cells, two aging rat models, and the elderly. HMGB1 acts as molecular scissors in producing DNA gaps. Increased gaps consolidated DNA durability, leading to DNA protection and improved aging features in senescent cells and two aging rat models similar to those of young organisms.
Similar to other DNA modifications such as 5-methylcytosine that can be either epigenetic marks or DNA damage, both pathological DNA breaks and physiological DNA gaps are DNA modifications with the same DNA structure; however, pathological DNA breaks are DNA damage, and the physiological DNA gaps are epigenetic marks. By evaluating the correlation between Youth-DNA-GAPs and age, we concluded that Youth-DNA-GAPs are a ubiquitous DNA change existing in a wide range of eukaryotic cells, including yeast, rodents, and humans. Additionally, the reduction of Youth-DNA-GAPs varies based on the aging degree and this decrease can result from chemical-induced or natural aging. The reduction of Youth-DNA-GAPs was associated with aging phenotypes regardless of cause. In rats, decreased DNA gaps were found in both natural and D-gal-induced aging groups.
In yeast, a strong correlation was observed between the reduction in Youth-DNA-GAPs and viability in aging yeast cells. So the gap reduction is rather a marker of biological than chronological aging. This study showed a negative relationship between the gaps and the number of senescence cells. Moreover, we found a similar reduction in 30-month-old naturally and 7-month-old D-gal-induced aging rats. Given these consistent data from different eukaryotic organisms, it suggests that the Youth-DNA-GAP is a marker of phenotype-related aging degree