Biology Reference
In-Depth Information
D. BER/SSBR in Mammalian Mitochondria
The mitochondria are the major site of ROS generation in aerobic organ-
isms and thus their genomes are continuously exposed to oxidative damage.
Furthermore, lack of protective histones makes the mitochondrial DNA more
susceptible to oxidative damage than the nuclear genome. Repair of oxidized
bases and SSBs via both SN-BER and LP-BER has been established in
mammalian mitochondria.
55-57
The early mitochondrial BER proteins, all
encoded by nuclear genes, are usually isoforms of the nuclear proteins, generated
due to alternate RNA splicing or proteolytic cleavage. Among the DGs, OGG1,
NTH1, and NEIL1 have been shown to localize in the mitochondria.
58-60
We
have shown that an N-terminal truncation product of APE1 is present in mam-
malian mitochondria.
61
Recent studies have shown the presence of TDP1 and
aprataxin in mitochondria.
62,63
In contrast to the sharing of early BER proteins
between nucleus and mitochondria, DNA polymerase
g
(Pol
g
), the only DNA
polymerase in mammalian mitochondria, is required for both mt genome repli-
cation and repair.
64
A splice variant of nuclear LigIII
a
functions similarly in both
mt genome replication and repair.
25
Although mitochondrial BER/SSBR was
initially thought to be a simple process involving only a few essential enzymes,
recent studies have demonstrated the presence of several additional nuclear
BER/SSBR components in mitochondria.
65
II. Complexity and Sub-pathways of BER/SSBR
Complete nuclear BER/SSBR that requires only four or five enzymes could
be demonstrated
in vitro
. However, recent studies have revealed that BER is
far more complex, involving a network of distinct cell cycle dependent as well
as genome region-specific repair sub-pathways and could also involve several
non-BER proteins.
66,67
A. Preferred and Backup Sub-pathways
The overlapping substrate specificity of DGs and the lack of strong pheno-
types associated with their individual deficiency suggest that these enzymes
have preferential and backup functions. Mouse mutants individually lacking
OGG1, NTH1, NEIL1, or MYH and the cells derived thereof are viable, while
combined deficiency of two DGs (e.g., NEIL1 and NTH1 or OGG1 and MYH)
strongly increases cancer susceptibility.
68-73
We postulate that these enzymes
with the unusual plasticity of their catalytic pockets can carry out excision of
diverse damaged bases in DNA, which is consistent with their catalytic ineffi-
ciency. However, the choice of the DG-initiated BER sub-pathway for the
same lesion may also depend on the cellular state.
