DNA damage is involved in degenerative aging, though there remains some debate over exactly how it can contribute meaningfully to widespread tissue dysfunction over and above the increased risk of cancer. Near all mutational damage to DNA is promptly repaired, while most of the lasting mutations occur in unused regions of the genome, in somatic cells with few divisions remaining. While most mutations can thus produce little harm, one possible path to broader damage results from mutations occurring in stem cells, which can spread widely throughout tissue to form overlapping patterns of mutations known as somatic mosaicism. There is some initial evidence for this to contribute to age-related conditions and loss of function. A more radical possibility is that repeated efforts to repair more severe forms of DNA damage, regardless of whether successful or not, deplete factors needed to maintain youthful control over genome structure and gene expression, and this gives rise to the characteristic changes observed in cells in aged tissues.
What can be done about stochastic DNA damage occurring in different places in different cells? Repairing this damage seems challenging, a project for the more distant future. Slowing down the accumulation of unrepaired damage seems more feasible, largely a matter of identifying crucial proteins in DNA repair machinery and providing more of them. Today's open access paper is an example of this approach. If, however, it is the case that even successful repair efforts inexorably give rise to changes in genome structure and cell behavior, this may not be all that effective in slowing aging. Reducing cancer incidence, yes, as that is absolutely driven by the burden of unrepaired mutational damage, but perhaps not so great for the rest of aging.
DNA damage is a serious threat to cellular viability, and it is implicated as the major cause of normal ageing. Hence, targeting DNA damage therapeutically may counteract age-related cellular dysfunction and disease, such as neurodegenerative conditions and cancer. Identifying novel DNA repair mechanisms therefore reveals new therapeutic interventions for multiple human diseases.
In neurons, non-homologous end-joining (NHEJ) is the only mechanism available to repair double-stranded DNA breaks (DSB), which is much more error prone than other DNA repair processes. However, there are no therapeutic interventions to enhance DNA repair in diseases affecting neurons. NHEJ is also a useful target for DNA repair-based cancer therapies to selectively kill tumour cells.
Protein disulphide isomerase (PDI) participates in many diseases, but its roles in these conditions remain poorly defined. PDI exhibits both chaperone and redox-dependent oxidoreductase activity, and while primarily localised in the endoplasmic reticulum it has also been detected in other cellular locations. We describe here a novel role for PDI in DSB repair following at least two types of DNA damage. PDI functions in NHEJ, and following DNA damage, it relocates to the nucleus, where it co-localises with critical DSB repair proteins at DNA damage foci. A redox-inactive mutant of PDI lacking its two active site cysteine residues was not protective, however. Hence, the redox activity of PDI mediates DNA repair, highlighting these cysteines as targets for therapeutic intervention.
The therapeutic potential of PDI was also confirmed by its protective activity in a whole organism against DNA damage induced in vivo in zebrafish. Hence, harnessing the redox function of PDI has potential as a novel therapeutic target against DSB DNA damage relevant to several human diseases.
View the full article at FightAging
