Molecular medicine-Premature Aging Associated with Defects in DNA Repair or Increased Oxidant Status

DNA damages are so frequent (Table 1)
that total absence of DNA repair of a
common damage is likely to be incompatible
with life. If a DNA repair pathway
lacks an essential enzyme, but the missing
enzyme can be, at least, partially compensated
for by a similar enzyme, then
repairmay be adequate to allow sufficient
survival and growth to show premature
aging. This will also occur if a particular
DNA damage is preferentially repaired
by one pathway, but another repair pathway,
with less efficiency, also repairs
that damage.
1. Helicase. There are at least 31 human
enzymes that are helicases or contain
helicase-motif domains. Helicases are
enzymes that unwind and separate the
strands of DNA, usually using the hydrolysis
of ATP to provide the necessary energy.
Some enzymes with multiple helicasemotif
domains only act as ATPases, providing
energy to DNA-related processes.
Helicases or enzymes with helicase-motif
domains participate in DNA repair, DNA
replication, and DNA recombination. Usually,
the helicase activity is specific for a
particular DNA configuration. Some helicases
involved in particular DNA-repair
pathways may be partially replaceable, at
least at a low level, by other helicases. That
may be why five genes, which code for
enzymes with helicase functions, or helicase
motifs plus an ATPase function, and
which are required in different DNA repair
pathways, when genetically defective,
cause syndromes characterized by early
aging in humans (Table 3). These syndromes
areWerner syndrome, Bloom syndrome,
Rothmund–Thomson syndrome,
Trichothiodystrophy and Cockayne syndrome
(Table 3). Similarly, in the mouse,
a defect in the Ku-80 gene, which normally
activates the Ku-70 helicase function, results
in an early aging phenotype (Table 3).
The different helicases listed in Table 3
have specificities for HRR, NHEJ, NER,
TCR or BER, so that defects in each of
these DNA repair pathways may allow
accumulation of different types of DNA
damage, each type being able to contribute
to premature aging.
2. Topoisomerase. Topoisomerases interact
with helicases in DNA repair, recombination,
and replication. When a helicase
64 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 reattachments
in DNA to relieve supercoiling.
There are a number of topoisomerases
in mouse and human cells. The different
topoisomerases interact specifically with
different helicases. However, some topoisomerases
may be partially replaceable by
another topoisomerase at a low level. In the
mouse, a mutant lacking topoisomerase
IIIβ develops to maturity but shows
early aging (Table 3). Topoisomerase IIIβ
interactswith humanRecQ5β helicase and
is thought to act inDNArepair, replication,
or recombination (Table 3).
3. ERCC1. Excision Repair Cross Complementing
1 (ERCC1), 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 homology
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
Fig. 1.
4. p53. Similar to helicase and topoisomerase,
p53 occurs as one of a family of
enzymes, p53, p63, and p73 (and both p73
and p63 have multiple isoforms), which
share significant homology and have similar
functions. In particular, p73 has a role
in activating DNA repair enzymes and in
carrying out apoptosis in the face of excess
DNA damage (see below in Fig. 3).
Thus, loss of p53 may, in part, be compensated
for by functions of p73 and/or p63.
In Section 1.3.4, we briefly discussed an
overactive form of p53 that causes early aging.
This mutant form of p53 has its effect
in the presence of a wild-type p53 (a heterozygous
situation) where it may increase
some functions detrimental to the cell. Although
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 increase
DNA damage through increases in
ROS. In addition, a p53 knockout mouse,
lacking all functions of p53, including its
functionality in three DNA repair pathways
(NER, BER, and HRR), is also viable
but ages prematurely (Table 3).
5. MsrA. 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 ).