Biology Reference
In-Depth Information
overall organism health, the expression of BER proteins must be tightly
controlled and regulated, with many proteins of the BER pathway showing
temporarily increased protein expression in response to cellular DNA damage
or the cell cycle.
11
There are many examples in primary cancers where the activity, expression,
or localization of specific BER proteins is altered or lost, providing evidence
not just for the regulation of BER but also for the biological consequences
associated with its deregulation. For example, in a subset of human lung cancer
tumors, nuclei show increased thymine glycol DNA glycosylase (NTHL1) and
8-oxoguanine DNA glycosylase (OGG1) repair activity, while the same is
reduced in their mitochondria.
12,13
In gastric cancers, the enzyme NTHL1 is
often lost in the nucleus, resulting either from the global downregulation of
steady-state protein levels or, as observed in a significant number of primary
gastric cancers, from NTHL1 becoming abnormally localized to the cytoplasm
rather than the nucleus.
14,15
There are further examples of BER dysfunction in
neurodegenerative disorders.
16,17
For example, the activities of both the
human uracil DNA glycosylase (UNG) and OGG1 are decreased in Alzheimer's
patients.
18
B. Regulation of BER: Current Concepts
and Observations
As aberrant BER activity occurs in both primary cancers and neurodegen-
erative disorders, perhaps contributing to the development of disease, regula-
tion of BER protein function must be tightly regulated. This regulation of BER
proteins has been proposed to occur through a variety of different mechanisms
including transcriptional control, posttranslational modification, protein local-
ization, and protein-protein interactions (
Table I
).
163
Each of these mecha-
nisms can contribute to regulation and therefore their integration can result in
a diverse range of effects on the proteins involved.
19-59,61-99,102-162
Changes in the steady-state transcript level of several BER proteins occur in
a cell cycle-dependent manner while other BER proteins show such a response
under increased oxidative stress (
Table I
).
11
For example, changes in transcript
level have been documented for
N
-methylpurine DNA glycosylase (MPG),
NTHL1, UNG, and human AP site-specific endonuclease (APEX1), in a cell
cycle-dependent manner, increasing 2.5- to 3.5-fold during G
1
and decreasing
to basal levels following mitosis.
26
On the other hand, the mRNA levels of
NTHL1, OGG1, and APEX1 are increased by exposure to hydrogen peroxide
and other reactive oxygen species (ROS) by as much as threefold.
68,108,164
Protein-protein interactions involving BER proteins are numerous and
have varied effects including increasing the efficacy of repair in mammals or
linking BER to different pathways such as nucleotide excision repair (NER) or
