Abstract
A definitive consequence of the aging process is the progressive deterioration of higher cognitive functions. Defects in DNA repair mechanisms mostly result in accelerated aging and reduced brain function. DNA polymerase µ is a novel accessory partner for the non-homologous end-joining DNA repair pathway for double-strand breaks, and its deficiency causes reduced DNA repair. Using associative learning and long-term potentiation experiments, we demonstrate that Polµ−/− mice, however, maintain the ability to learn at ages when wild-type mice do not. Expression and biochemical analyses suggest that brain aging is delayed in Polµ−/− mice, being associated with a reduced error-prone DNA oxidative repair activity and a more efficient mitochondrial function. This is the first example in which the genetic ablation of a DNA-repair function results in a substantially better maintenance of learning abilities, together with fewer signs of brain aging, in old mice.
Highlights
Non-homologous end-joining (NHEJ) is a fundamental pathway for the repair of double-strand breaks (DSB) in mammals
It is currently thought that, during the NHEJ reaction, Polm will be used as a backup to other PolX members that are less prone to introducing mutations in the DNA
Polm2/2 and wild-type animals (n = 10 per group) were classically conditioned, using a tone as a conditioned stimulus (CS) and an electrical shock presented to the supraorbital nerve as an unconditioned stimulus (US; Figure 1)
Summary
Non-homologous end-joining (NHEJ) is a fundamental pathway for the repair of double-strand breaks (DSB) in mammals. The structure of all members of the PolX family has been resolved [9], and a working model for Polm action during end-bridging of broken DNA ends (Text S1and Figure S1) proposed [9], [10]. According to this model, and considering the ability of Polm to carry out untemplated deoxynucleotide and ribonucleotide insertions [11], [12], Polm would behave as an error-prone DNA repair polymerase. We have evaluated young (3-month-old) and aged (18-month-old) wild-type or Polm2/2 mice in associative learning and long-term potentiation (LTP) tests [17]
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