60
Aging and Sex, DNA Repair in
degradation and some repair reactions.
If cellular genes that code for enzymes
involved in the replacement of damaged
proteins are themselves damaged, then
damaged proteins may not turn over
as rapidly, and protein damages may
become important as they accumulate with
age. Table 2 shows that insertion of an
extra gene encoding bovine methionine
sulfoxide reductase (MsrA) in the fruit fly
genome, which helps repair oxidatively
damaged proteins, leads to life span
extension. Consistent with this, MsrA,
when defective in the mouse, results in
early aging (Table 3).
4.
p66Shc
.The
p53
gene has a central
role in response to DNA damage. The
p53 protein is directly active in three
forms of DNA repair (NER, BER, and
HRR). When there is no externally induced
DNA damage, p53 has a half-life of
o
n
l
y5t
o4
0m
i
n
u
t
e
ss
i
n
c
es
p
e
c
i
F
c
enzymes target p53 for degradation. Thus,
p53 is kept at a low level when there
is no DNA damage. However, upon
exposure of a cell to DNA-damaging
agents, p53 becomes metabolically stable
and, in addition, more copies of it are
produced in the cell. In the presence
of various types of DNA damage, p53
undergoes modiFcations at some of the
18 different sites within the protein. Some
of these modiFcations [phosphorylations,
acetylations, poly(ADP-ribosyl)ations, or
sumoylations (covalent attachments of
small ubiquitin-like proteins) allow the
p53 protein to act as a regulatory agent,
activating numerous other genes, carrying
out different responses to different kinds
or levels of DNA damage. The p53 protein
can regulate or act in at least four major
types of responses to DNA damage (acting
as a ‘‘master switch’’), and which action or
transactivation (regulating the induction
of other genes) it performs depends on
the level and type of DNA damage. p53
can (1) send the cell into cell cycle arrest
(
t
oa
l
l
owe
x
t
r
at
im
ef
o
rr
ep
a
i
ro
fDNA
damage); (2) act directly in DNA repair
(see ±ig. 1 for where p53 acts in NER);
(3) cause the cell to switch into a cell
suicide mode (apoptosis); or (4) cause the
cell to produce higher levels of ROS
(apparently as a preliminary to entering
the cell suicide mode of apoptosis). When
acting to increase the internal level of ROS
and entry into apoptosis, p53 acts through
another gene it controls,
p66Shc
.
When a mouse embryo is produced
with both copies of its
p66Shc
gene
inactive (a p66Shc ‘‘knockout’’), mouse
embryo Fbroblast cells derived from it
have intracellular levels of ROS reduced by
about 40%. Consistent with this reduction
in ROS, there is also greatly reduced
oxidative damage accumulation in both
nuclear and mitochondrial DNA of these
cells. A similar reduction in nuclear and
mitochondrial DNA damage is seen
in
vivo
in the tissues of lung, spleen, liver,
and skin in 3- and 24-month-old
p66Shc
knockout mice, although there is no
reduction in the brain, where
p66Shc
is
not normally expressed. Cells of these mice
are inhibited from undergoing apoptosis
after cellular oxidative damage (when
challenged with externally applied H
2
O
2
).
Knockout mice without
p66Shc
show
life span extension without any notable
increase in cancer or other pathological
defects (Table 2). Mice with a type of
overactive p53
(an
increase
in
some
p53 functions) and intact
p66Shc
show
early aging (Table 3). On the other hand,
removal of all p53 functions (some of
which are protective in DNA repair) also
results in early aging (Table 3).
5.
PARP
.D
N
Ad
am
a
g
e
sc
a
u
s
e
db
y
alkylating agents (such as those that
methylate
guanine,
discussed
above),
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