70
Aging and Sex, DNA Repair in
2
DNA-repair Pathways and Their Relation
to Aging
2.1
NER (Nucleotide Excision Repair)
NER repairs DNA with helix-distorting
single-strand
DNA
damages,
includ-
ing
some
oxidative
damages
such
as
the
cyclopurine
8,5
0
-(S)-cyclo-2
0
-
deoxyadenosine. About 30 proteins are in-
volved in NER. The key steps in the process
(Fig. 1) are (1) recognition of a DNA defect;
(2) recruitment of an initial repair com-
plex; (3) preparation of the DNA for repair
through the action of helicases; (4) incision
of the damaged strand on each side of the
damage with release of the damage in a
single-strand fragment about 24 to 32 nu-
cleotides long; (5) ±lling in of the gap by re-
pair synthesis; and (6) ligation to form the
±nal phosphodiester bond. The two sub-
pathways of NER, TCR, and GGR, are ini-
tiated somewhat differently, but after initi-
ation most enzymatic steps are the same.
Individuals with the inherited disease xe-
roderma pigmentosum (XP) are defective
in NER and are sensitive to UV radia-
tion. About 25% of such patients also have
neurodegeneration attributed to neural ox-
idative damage. XP patients have defects
in one of seven
XP genes
,
XPA
through
XPG
, with some of their roles indicated
in Fig. 1. A number of speci±c mutations
resulting in defects in XPD, a helicase,
cause a milder disease than XP, called
trichothiodystrophy
, and these mutations
cause early aging (Table 3). XPA or XPC,
both involved in the recognition of DNA
damage (Fig. 1), when defective, do not
appear to affect aging (Table 4), perhaps
because if either is defective, compensa-
tion can occur to some extent. However,
a double-mutant mouse, defective with
a trichothiodystrophy-causing XPD muta-
tion plus an XPA mutation, ages more
rapidly than a mouse with a single XPD
defect.
ERCC1, an endonuclease, associates
with XPF, and then this pair associates
with the initial repair complex to carry out
an incision on a strand carrying the DNA
damage. Defects in ERCC1 cause early ag-
ing (Table 3). CSB is an enzyme with seven
helicase motifs and an ATPase function.
The ATPase function is required in TCR
of NER. CSB interacts with the TFIIH
complex [a transcription complex (tran-
scription factor II H)] required in NER
(Fig. 1), as well as with XPA, another NER
protein (Fig. 1). Patients with alterations
in CSB show early aging (Table 3). p53 af-
fects the helicase step of NER and is also
required for apoptosis when damage re-
quiring NER is excessive (Fig. 1). Defects
in p53 cause early aging (Table 3). Thus,
at least four NER enzymes (XPD, CSB,
p53, ERCC1), when defective, may allow
helix-distorting DNA damages to accumu-
late more rapidly than normal, leading
to premature aging. In addition, the p53-
regulated pathway of apoptosis (Fig. 1),
perhaps triggered by helix-distorting DNA
damages, if defective in p66Shc, results in
life span extension (Table 2).
2.2
BER (Base Excision Repair)
BER protects mammalian cells against
single-base DNA damage by methylating
agents, most oxidative damages, and a
large number (about 9,000 per cell per
day – see Table 1) of spontaneous depuri-
nations. BER is mediated through at least
two subpathways, one involving removal
and replacement of a single nucleoside
and the other involving a longer patch
repair of 2 to 15 nucleotides. Repair
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