Aging and Sex, DNA Repair in
63
ionizing radiation (which produces DNA
single- and
double-strand breaks
and
oxidative damages), and ROS result in
rapid activation of an enzyme called
poly(ADP-ribose)
polymerase
,o
rP
A
R
P
.
PARP, similar to p53 discussed above,
has a role as a ‘‘master switch’’. PARP
can (1) act directly in one form of DNA
repair, BER, (2) control the function of
many other proteins by catalyzing the ad-
dition of ADP-ribose branched polymers
onto them (either activating or repressing
their function), and (3) trigger apoptosis
(cell suicide). In addition, PARP controls
new transcription or activities of a number
of genes affecting survival or apoptosis,
including p53. It was found that centenar-
ians (humans who have lived for more
than 100 years) have a modiFed form
of PARP, which is more efFciently acti-
vated than the PARP of noncentenarians
(Table 2), thereby apparently causing life
span extension. In addition, the maximal
poly(ADP-ribosyl)ation capacity (efFciency
of activation of PARP) in leukocytes of
13 mammalian species of different life
span was measured. There was a strong
correlation of PARP efFciency of activation
with species-speciFc life span.
1.4
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 incom-
patible with life. If a DNA repair pathway
lacks an essential enzyme, but the missing
enzyme can be, at least, partially com-
pensated for by a similar enzyme, then
repa
irmaybeadequatetoa
l
lowsufFc
ient
survival and growth to show premature
aging. This will also occur if a particu-
lar DNA damage is preferentially repaired
by one pathway, but another repair path-
way, with less efFciency, also repairs
that damage.
1.
Helicase
. There are at least 31 hu-
man enzymes that are helicases or con-
tain helicase-motif domains. Helicases are
enzymes that unwind and separate the
strands of DNA, usually using the hydroly-
sis of ATP to provide the necessary energy.
Some enzymes with multiple helicase-
motif domains only act as ATPases, pro-
viding energy to DNA-related processes.
Helicases or enzymes with helicase-motif
domains participate in DNA repair, DNA
replication, and DNA recombination. Usu-
ally, the helicase activity is speciFc for a
particular DNA conFguration. Some he-
licases involved in particular DNA-repair
pathways may be partially replaceable, at
least at a low level, by other helicases. That
may be why Fve genes, which code for
enzymes with helicase functions, or heli-
case motifs plus an ATPase function, and
which are required in different DNA re-
pair pathways, when genetically defective,
cause syndromes characterized by early
aging in humans (Table 3). These syn-
dromes are Werner syndrome, Bloom syn-
drome, Rothmund–Thomson syndrome,
Trichothiodystrophy and Cockayne syn-
drome (Table 3). Similarly, in the mouse,
a defect in the
Ku-80
gene, which normally
activates the Ku-70 helicase function, re-
sults in an early aging phenotype (Table 3).
The different helicases listed in Table 3
have speciFcities 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 inter-
act with helicases in DNA repair, recombi-
nation, and replication. When a helicase
previous page 63 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 65 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off