Aging and Sex, DNA Repair in
unwinds the two DNA strands of the
double helix, this introduces supercoiling
of the associated DNA. Topoisomerases
introduce controlled breaks plus reattach-
ments in DNA to relieve supercoiling.
There are a number of topoisomerases
in mouse and human cells. The different
topoisomerases interact speciFcally with
different helicases. However, some topoi-
somerases may be partially replaceable by
another topoisomerase at a low level. In the
mouse, a mutant lacking topoisomerase
develops to maturity but shows
early aging (Table 3). Topoisomerase III
interacts with human RecQ5
helicase and
is thought to act in DNA repair, replication,
or recombination (Table 3).
. Excision Repair Cross Com-
plementing 1 (
), when defective, is
another gene whose absence or truncation
causes an early aging phenotype in the
mouse (Table 3). ERCC1 functions in both
NER and interstrand cross-link repair (in
a step prior to HRR). ERCC1 has homol-
ogy with an endonuclease active in NER
in yeast, and that yeast endonuclease can
compensate for the loss of a topoisomerase
or a helicase. Thus, ERCC1 may have some
functional similarity to topoisomerase or
helicase in DNA repair. Conversely, loss
of ERCC1 may be partially compensated
for by a helicase or topoisomerase, or by
another endonuclease in mouse, so that a
defect in ERCC1 is not lethal but causes
early aging. ERCC1 primarily functions in
NER as an endonuclease as illustrated in
±ig. 1.
. Similar to helicase and topoiso-
merase, p53 occurs as one of a family of
enzymes, p53, p63, and p73 (and both p73
and p63 have multiple isoforms), which
share signiFcant homology and have sim-
ilar functions. In particular, p73 has a role
in activating DNA repair enzymes and in
carrying out apoptosis in the face of ex-
cess DNA damage (see below in ±ig. 3).
Thus, loss of p53 may, in part, be compen-
sated for by functions of p73 and/or p63.
In Section 1.3.4, we briefly discussed an
overactive form of p53 that causes early ag-
ing. This mutant form of p53 has its effect
erozygous situation) where it may increase
some functions detrimental to the cell. Al-
though it is not known which functions
it increases, an increase of p66Shc under
p53 control could reasonably be expected
to cause early aging, since it would in-
crease DNA damage through increases in
ROS. In addition, a p53 knockout mouse,
lacking all functions of p53, including its
functionality in three DNA repair path-
ways (NER, BER, and HRR), is also viable
but ages prematurely (Table 3).
. As discussed in Section 1.3.3,
if cellular genes, which code for activity
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. Added activity
of MsrA in the fruit fly gave greater
longevity. Defective MsrA in the mouse
caused early aging (Table 3).
Normal Aging in spite of Certain Defects in
DNA Repair or Increases in Antioxidant
Enzyme Production
If a DNA repair pathway lacks an enzyme,
compensated for by a similar enzyme,
then repair may be sufFcient to allow
survival, growth, and normal aging. While
such fairly good compensation may allow
normal aging, the repair of DNA damages
would still be less than if the repair
pathway were intact, and that could lead to
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