DNA Polymerase‐β May Be the Main Player for Defective DNA Repair in Aging Rat Neurons

Abstract

A close relationship between the DNA repair potential of various organisms and their rate of aging has been long suspected. We have been looking into the steps of the DNA repair process in isolated neurons from rats of different ages. Unscheduled DNA synthesis (UDS) was low in aging neurons, and also the response of these cells to raise their DNA repair capacity against a mutagenic challenge was poor. Attempts to identify the possible defective locus in the overall DNA repair pathways indicated that the step involving DNA polymerase may be defective. The activity of DNA polymerase‐β, the most predominant DNA polymerase in neurons that is generally considered to be a short‐patch repair enzyme, shows a significant decrease in aging neurons. Northern and Southern blotting and immunotitration experiments suggest that there may be an accumulation of inactive β polymerase molecules in the aging rat brain. Most recent preliminary studies reveal significant 3′‐5′ exonuclease activity in rat neurons at all ages. However, extension of a primer in a synthetic oligo duplex, either with a mismatch or correct base pair at the 3′ end of the primer, was low in neurons of any age and was very poor (almost undetectable) in older ones. Supplementation of neuronal extracts with pure polymerase enzyme revealed that only polymerase β, but not polymerase α, was able to increase the primer extension activity significantly in old neurons. These findings are taken to indicate an age‐dependent decline in the DNA repair capacity of neurons and that DNA polymerase β is a key player in the DNA repair mechanisms of nerve cells.

Base excision repair in the mammalian brain: Implication for age related neurodegeneration

“…Consistent with this decrease, activity on a gap filling substrate, used to measure Polβ activity, was reduced to comparable levels, and western results showed a decrease in Polβ protein levels to approximately 50% of the levels seen in young animals. These findings have been supported by a decline in DNA repair activity in protein extracts from neurons taken from old rats (Rao et al 2001;Rao et al 2000), a feature that can be restored to normal by supplementation with purified Polβ. It is unclear whether a sustained reduction in Polβ has an impact on behavioral parameters.…”

Tissue-specific differences in the accumulation of sequence rearrangements with age

“…The efficiency and fidelity of some DNA repair pathways such as base excision repair and NHEJ have been shown to decrease with age [4][5][6][7]66,67]. Here, we measured recombination using two independent methods: we assessed the rate of recombination at the FYDR locus (which is designed to measure not only exchanges between sister chromatids, but also gene conversions in the absence of crossovers), and we also measured the frequency of SCEs.…”

Nuclear DNA Damage as a Direct Cause of Aging

“…48 DNA polymerase ß activity in the livers of old rats was found to be half that of young rats. 50 Further study on aging rat brain neurons found that both DNA polymerase ß and DNA ligase were needed to restore BER.…”