Aging and Sex, DNA Repair in
73
activity (Table 2). PARP has a central role
in recruitment of the BER multiprotein
complex (Fig. 2). p53 stimulates BER
through interaction with ref-1 and DNA
polymerase
β
(Fig. 2). Mice defective in
p53 show early aging (Table 3).
p66Shc, when absent, causes life span
extension of mice raised under protected
laboratory conditions, and also longer sur-
vival of mice challenged by the oxidatively
damaging compound paraquat. Mouse
embryo ±broblast cells that are defective
in p66Shc, when treated with H
2
O
2
,have
much less apoptosis than wild-type cells
treated with H
2
O
2
. This would be expected
from the known role of p66Shc in the
p53-controlled apoptosis pathway shown
in Fig. 2. In addition, a defect in p66Shc
causes reduced intracellular constitutive
levels of ROS in lung, spleen, liver, and
skin cells, where p66Shc is normally active.
These reduced ROS levels are reflected in
lower levels of oxidative DNA damage both
in nuclear DNA and mitochondrial DNA of
these tissues (both types of DNA damage
normally repaired by BER).
Thus, two gene products involved in
carrying out BER (CSB and p53), when
defective, cause early aging. One gene
product essential for BER, PARP, when
more active, allows longer life span.
One gene product, p66Shc, causes more
DNA damages, needing BER when it is
active. When p66Shc is absent, there are
fewer DNA damages and there is life
span extension.
2.3
HRR (Homologous Recombinational
Repair)
Double-strand breaks, interstrand cross-
links, and DNA damages blocking a
replication fork can be repaired by one
of two pathways, HRR or NHEJ. The
selection of pathway depends on whether
the cell has replicated its DNA (the
S
/
G
2
phase of the cell cycle), so that
sister chromatids are available (which fa-
vors HRR), or whether the cell is in
G
0
/
G
1
(which favors NHEJ). The choice
of
HRR
or
NHEJ
also
depends
on
whether the cell is from embryonic tis-
sue (which favors HRR) or from adult
tissue (which, for certain damages, fa-
vors NHEJ). While HRR is especially
promoted during meiosis (where there is
ordinarily pairing and recombination be-
tween homologous chromosomes), HRR
is also important in somatic cells. De-
fects in enzymes of HRR, including WRN
(Werner syndrome), the RECQ3 helicase,
and BLM (Bloom syndrome), the RECQ2
helicase, cause genetic instability and can-
cer (Table 3).
HRR is initiated through a multimeric
complex, the BRCA1-associated genome
surveillance complex (BASC). BASC in-
cludes the DNA repair proteins BRCA1,
MSH2
,MSH6
,MLH1
,ATM
,BLM
,and
the RAD50-MRE11-NBS1 protein com-
p
lex
,someo
fwh
ich(BRCA1
,ATM
,and
BLM) are indicated in Fig. 3. BASC is
thought to act as a sensor for DNA
damage, to which it binds. Depending
on the type or amount of double-strand
damage, BASC signals for (1) initiation
of further steps of HRR, (2) interaction
with the ‘‘master switch p53’’ to turn
on
cell
cycle
arrest
(to
allow
more
time for HRR), (3) apoptosis through
the p53/p66Shc pathway, or (4) apoptosis
through the p73 pathway (Fig. 3). As in-
d
i
c
a
t
edinF
ig
.3
,BRCA1andp
53h
a
v
e
a type of feedback loop whereby BRCA1
may activate p53, and p53 may, in turn,
inhibit BRCA1.
Further steps of HRR, shown in Fig. 3,
involve (1) recruitment of a second homol-
ogous chromosome, (2) Rad51-dependent
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