Biology Reference
In-Depth Information
A. Cancer
Varying degrees of cancer proneness have also been demonstrated with
BER/SSBR defects. A connection between a repair defect and cancer risk is
established for the hMYH.
144,145
The genetic locus of OGG1 (3p26.2) is
frequently lost in various human cancers, including lung and renal cell can-
cer.
146,147
Polymorphic variants of OGG1 (S326C and R46Q) have also been
identified within the population that demonstrate mild reductions in enzymatic
activity.
148,149
However, there are conflicting epidemiological reports regarding
the association of these variants with cancer susceptibility.
150
While an increase
in the levels of 8-oxoG and mutation frequency was evident in OGG1-
null mice, no significant enhancement of spontaneous tumor incidence was
observed.
68,151,152
Interestingly, the NEIL1-knockout mouse was found to
exhibit clinical features distinctly similar to the human metabolic syndrome,
with extensive fat deposits in various tissues.
73
As already mentioned, because
of the backup functions of mammalian DGs, mice lacking a single DG do not
show a significant phenotype, and only when two or more DGs are simulta-
neously eliminated do symptoms appear. For example, when both MYH and
OGG1 were deleted, the resulting double-knockout animal (unlike the single
knockouts) exhibited an increased predisposition to spontaneous tumorigene-
sis, particularly lung and ovarian tumors, and lymphomas.
153
It is likely that
single DG-null animals possess compensatory mechanisms for base damage
tolerance that prevent disease manifestation,
154
which could explain why the
association of BER defects with cancer proneness appears less compelling.
Furthermore, specific environmental factor(s) may foster the observed disease
susceptibility in DG-deficient animals/cells.
155
In contrast to the weak association of DGs with cancer risk, deficiencies in
downstream BER/SSBR proteins, for example, Pol
b
, APE1, or XRCC1, as well
as FEN1 or a DNA ligase (I or III), lead to embryonic lethality in mice,
suggesting an absolute requirement for the BER process during embryonic
development.
156-159
Furthermore, inactivation of Pol
b
mutations has been
strongly associated with cancer. Genetic analysis revealed that an astonishing
30% of human tumors express Pol
b
variants,
160
many of which (e.g., K289M
and I260M) exhibit reduced polymerase fidelity.
161
APE1 and XRCC1 variants
have also been found in numerous epidemiology studies to associate with
specific human cancers
162,163
; however, definitive conclusions could not be
drawn because of the small sample sizes.
164,165
B. Neurodegenerative Diseases
More than 200 neurological disorders with diverse etiologies and genetic
characteristics have been reported so far in humans, many of which have been
linked to inherited or acquired defects in one of the DNA repair pathways,
