72
Aging and Sex, DNA Repair in
nick. The nick then activates PARP, which
catalyzes formation of poly(ADP-ribose)
(polyAR) branched chain polymers, us-
ing the adenosine diphosphate ribose part
of nicotinamide adenosine dinucleotide
(NAD
+
) with the release of nicotinamide
(NAM) (Fig. 2). PolyAR is attached to nu-
merous nearby proteins, including PARP
itself and p53. Proteins modi±ed by pol-
yAR gain or lose functions. Fig. 2 in-
dicates alteration in the transactivation
role of p53 and its role in cell cycle ar-
rest and apoptosis after it is modi±ed
by polyAR. Subsequently, a multiprotein
complex (including XRCC1 and possibly
DNA polymerase
β
and DNA ligase III) is
recruited to the site by PARP, and repair
patch synthesis and DNA ligation com-
plete the process of BER (Fig. 2).
Individuals with Cockayne Syndrome
show premature aging. Mutant cells with
a defect in helicase motifs V or VI of
Cockayne syndrome B (CSB) are defective
in BER of one common oxidized base, 8-
hydroxyguanine, but not defective in BER
of two other oxidized bases, thymine glycol
or 5-hydroxy-dCytosine. CSB is involved in
the speci±c glycosylase step for BER of
8-hydroxyguanine (Fig. 2).
Centenarians
(individuals
who
have
lived for more than 100 years) appear to
have an altered PARP with higher speci±c
Ref-1
p53
Apoptosis
Cell cycle
arrest
BER multiprotein
complex
PARP-1
NAD
+
NAD
+
NAD
+
NAD
+
NAD
+
PolyAR
PolyAR
Ref-1
p53
pol
b
DNA with AP site
Glycosylase
NAM
NAM
NAM
NAM
NAM
DNA with
damaged base
Completion of
base excision repair (BER)
p66Shc
Fig. 2
Base excision repair (BER).
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