X-Message-Number: 25665
Date: Sun, 6 Feb 2005 05:26:59 -0800 (PST)
From: Doug Skrecky <>
Subject: DNA polymerase beta rejuvenates DNA repair

J Neurochem. 2005 Feb;92(4):818-23.
Reduced DNA gap repair in aging rat neuronal extracts and its restoration
by DNA polymerase beta and DNA-ligase.
  Abstract Synthetic deoxy-oligo duplexes containing short gaps of 1 and 4
nucleotides were used as model substrates to assess the DNA gap repair
ability of the neuronal extracts prepared from cerebral cortex of rats of
different ages. Our results demonstrate that gap repair activity in
neurons decreases markedly with age. The decreased activity could be
restored by supplementing the neuronal extracts with pure recombinant rat
liver DNA polymerase beta. High levels of DNA polymerase beta
supplementation resulted in gap-filling activity that proceeded
essentially through addition of nucleotides through a slow distributive
strand displacement mode to achieve full template length (32-mer).
However, at lower concentrations of DNA polymerase beta, the gap repair
takes place quickly through gap filling followed by ligation to
downstream primer, in an energy efficient manner. For this to happen, the
conditions required are the presence of 5'-PO(4) on the downstream primer
and supplementation of aging neuronal extracts with DNA-ligase in
addition to recombinant DNA polymerase beta. These results demonstrate
that aging neurons are unable to affect base excision repair (BER)
due to deficiency of DNA polymerase beta and DNA-ligase and fortifying
aged neuronal extracts with these two factors can restore the lost BER
activity.

[Could this be how CR affects cancer risk?]

DNA Repair (Amst). 2003 Mar 1;2(3):295-307
Caloric restriction promotes genomic stability by induction of base
excision repair and reversal of its age-related decline.
  Caloric restriction is a potent experimental manipulation that extends
mean and maximum life span and delays the onset and progression of tumors
in laboratory rodents. While caloric restriction (CR) clearly protects
the genome from deleterious damage, the mechanism by which genomic
stability is achieved remains unclear. We provide evidence that CR
promotes genomic stability by increasing DNA repair capacity,
specifically base excision repair (BER). CR completely reverses the
age-related d ecline in BER capacity (P<0.01) in all tissues tested
(brain, liver, spleen and testes) providing aged, CR animals with the BER
phenotype of young, ad libitum-fed animals. This CR-induced reversal of
the aged BER phenotype is accompanied by a reversal in the age-related
decline in DNA polymerase beta (beta-pol), a rate-limiting enzyme in the
BER pathway. CR significantly reversed the age-related loss of beta-pol
protein levels (P<0.01), mRNA levels (P<0.01) and enzyme activity
(P<0.01) in all tissues tested. Additionally, in young (4-6-month-old) CR
animals a significant up-regulation in BER capacity, beta-pol protein and
beta-pol mRNA is observed (P<0.01), demonstrating an early effect of CR
that may provide insight in distinguishing the anti-tumor from the
anti-aging effects of CR. This up-regulation in BER by caloric
restriction in young animals corresponds to increased protection from
carcinogen exposure, as mutation frequency is significantly reduced in CR
animals exposed to either DMS or 2-nitropropane (2-NP) (P<0.01). Overall
the data suggest an important biological consequence of moderate BER
up-regulation and provides support for the hormesis theory of caloric
restriction.

Mech Ageing Dev. 1998 Aug 14;104(2):133-48.
Improved DNA-repair parameters in PHA-stimulated peripheral blood
lymphocytes of human subjects with low body mass index.
  Clinically healthy subjects of the Indian population were divided into
three age groups: young, 8-14 years; adult, 20-35 years; old, > or = 55
years and were further classified based on body mass index (BMI) as
normal BMI (NBMI)> or =20 and low BMI (LBMI) between 16 and 18,
respectively. The ability of the peripheral blood lymphocytes from these
subjects to respond to PHA stimulation in vitro and DNA-repair
parameters, thereafter as a function of BMI and aging, were studied. The
DNA-repair markers like unscheduled DNA synthesis (UDS), activities of
DNA polymerase beta and of two endodeoxy-ribonucleases, (UV- and
AP-DNases) were assessed under different conditions. The LBMI group,
considered to be going through chronic but mild undernutrition, showed
higher repair capacity and exhibited no appreciable age-dependent decline
in DNA-repair potential as was seen in normal subjects. These results
correlate well with those seen in unstimulated human lymphocytes and also
confirm the observations made earlier in experimental animals, where
dietary restriction was shown to have beneficial effects on DNA-repair
capacity.

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