82
Aging and Sex, DNA Repair in
testes. The human RecA homolog carries
out the distinctive reactions of
E. coli
RecA protein, including DNA-dependent
hydrolysis of ATP, renaturation of com-
plementary strands, homologous pairing
of a single strand with duplex DNA, and
strand exchange. A pair of
recA
gene ho-
mologs of the lily,
lim15
and
rad51
,which
are also homologs of the yeast
dmc1
and
rad51
genes, were found by Terasawa and
coworkers in 1995. The
lim15
gene in lily is
speciFcally expressed in meiotic prophase
during microsporogenesis. Thus, in both
animals and plants, homologs of bacterial
recA
appear to have an important role in
meiotic recombination.
3.8
The Adaptive Function of Recombination
Appears to Be Removal of DNA Damage
DNA repair is probably the principal adap-
tive function of the RecA protein and its
homologs. RecA protein binding is largely
limited to regions in the DNA containing
suitable nucleation sites, especially single-
strand gaps. A variety of DNA damages
cause structural perturbations that provide
favorable nucleation sites.
About 100 ATPs are hydrolyzed for every
base pair of heteroduplex DNA generated
by RecA-mediated strand exchange. In
1993, Cox reviewed evidence that the
energy released by ATP hydrolysis is used
speciFcally to allow the strand-exchange
process to traverse damaged regions of
DNA. He argued that this use of ATP
is readily understood as an adaptation of
repair of DNA damage. Thus, the evidence
reviewed by Cox indicates that the adaptive
function of RecA homologs, acting during
meiosis, is DNA repair.
In humans, HRR is carried out by a
group of interacting proteins in which
the RecA homolog Rad51 has a central
role. Other proteins involved in HRR in
humans include the products of genes
BRCA1
,
BRCA2
,
ATM
,
ATR
,
FANCD2
,
HMLH1
,and
p53
.
These proteins appear to be responsible
for HRR during meiosis and for HRR
between sister DNA homologs in somatic
cells. HRR is employed in removing
a variety of DNA damages, particularly
double-strand damages such as double-
strand breaks and DNA cross-links. The
proteins named just above, involved in
HRR, also appear to use their DNA
damage recognition capability to induce
apoptosis (a form of programmed cell
death) when the number of DNA damages
in a cell is higher than those that can
be repaired. In somatic cells, apoptosis
is a protective mechanism for the whole
organism since it eliminates cells that
might otherwise survive despite having
unrepaired DNA damages, and upon
replication acquire mutations.
In fact, germ line mutations in genes
BRCA1
,
BRCA2
,
ATM
,
ATR
,
FANCD2
,
HMLH1
,and
p53
predispose individuals to
cancer. Cancer predisposition results from
an inadequate response to DNA damage
in somatic cells leading to increased mu-
tations, some of which cause progression
to malignancy. Thus, the central function
of these genes is to cope with DNA dam-
ages, either to repair the damages, or if
theirnumberinacellisunmanageable,to
induce apoptosis.
Males that are defective in
ATM
or
p53
are unable to respond appropriately to
DNA damage during meiosis, and, as a
likely result, they suffer from low sperm
quantity and quality. The high effective-
ness of DNA damage removal processes
during normal meiosis is reflected in mice,
where there is a one-third lower rate of
mutation in germ cells compared to that
in somatic cells.
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