Correlation Between Deoxyribonucleic Acid Excision-Repair and Life-Span in a Number of Mammalian Species

Abstract

The ability of fibroblasts to perform unscheduled DNA synthesis (a measure of excision-repair) after UV irradiation was measured radioautographically for seven species at several times after several UV fluences. Both the initial rate and the maximum incorporation of[3H]dThd increased with the life-span of the species (shrew, mouse, rat, hamster, cow, elephant, man). Unscheduled DNA synthesis was approximately proportional to the logarithm of life-span.If an animal's cells are exposed to a constant level of physical and chemical damages per unit time, they will accumulate damages at rates dependent on the efficiencies of the repair systems for the individual damage components. If the systems are inefficient, the level of damage in DNA will increase relatively rapidly, and the resulting aberrant macromolecular synthesis may lead to cellular malfunction (and the animal's death). This point of view leads to the prediction that there is correlation between the life-span of a species and its overall ability to (3), but nondividing cells such as rabbit retinal (4) or dog neuronal cells (5) were able to repair ionizing radiation breaks as well as fibroblasts. The cells from progerioid individuals were observed to be defective in the ability to rejoin DNA strand breaks (6) but normal for repair replication after UV irradiation (7).Excision of DNA damage due to UV irradiation has been measured for a number of different species (8, 9). UV radiation is a convenient model insult because its effects on cellular DNA can be well quantitated. The excision-repair of damaged UV-irradiated DNA has been analyzed by a number of different techniques (8-11), such as (a) the actual removal of cyclobutyl pyrimidine dimers (excision), (b) repair replication (the incorporation of radioactive label into parental DNA during repair), (c) unscheduled DNA synthesis (the synthesis of DNA during non-S periods of the cell), and (d) the photolysis of bromodeoxyuridine incorporated into parental DNA during repair. Although these techniques measured different parameters, they all seem to give similar estimates of excisionrepair (12, 13), and it has been shown with several of them that normal human cells (14-16) and cells from cow (17) are very efficient at dimer excision. However, dimer excision in hamster cells is barely detectable (13)

A new theory of carcinogenesis

“…In general, we might therefore expect excision to be the preferred pathway in man and other large mammals. This is in agreement with the observations of Hart & Setlow (1974), who showed that there is a clear positive correlation between longevity (which is also related to body size), and the amount of excision repair in UV-irradiated cultured fibroblasts from a variety of mammals. In man, the disease conferring sensitivity to sunlight, xeroderma pigmentosum, is known to block excision repair of pyrimidine dimers (Cleaver & Bootsma, 1975).…”

Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity

“…In this context, it is interesting to note that differences in expression in DDB2 between rodents and primates have been reported to play a role in protection against DNA damage and carcinogenesis (Alekseev et al 2005). Although DNA repair was not among our top GO categories, we speculate that the evolutionary pressure on a few specific proteins involved in DNA repair or DNA damage response could be an optimization leading to a better regulation of damage, cell cycle, and genome stability and hence to a longer lifespan, in line with results suggesting higher DNA repair in longer-lived mammals (Hart and Setlow 1974;Freitas and de Magalhães 2011).…”

“…One hypothesis is that long-lived species evolve better mechanisms to cope with different forms of molecular damage, including better repair mechanisms (Kirkwood and Austad 2000;Miller 2001). This view is supported by correlations between DNA repair and mammalian lifespan (Hart and Setlow 1974) and by evidence that cells from long-lived species are more resistant to some forms of stress (Harper et al 2007). …”

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

“…Several reports support this hypothesis. Hart and Setlow (1974), Francis et al (1981), Hall et al (1984), and Licastro and Walford (1985) have all demonstrated positive correlations between species maximum lifespan (MLSP) and UV-induced DNA damage repair in fibroblasts or lymphocytes. The pyrimidine dimers and photoproducts associated with UV radiation are removed by global nucleotide excision repair (NER).…”