Biology Reference
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increase and cells become sensitive to both hydrogen peroxide and methyl
methanesulfonate.
183
This finding provides evidence that the regulation of
BER proteins through dynamic localization is crucial in the maintenance of
genomic stability and suggests a possible mechanism for how BER proteins
become mislocalized in certain cancers.
12-15
III. Hypotheses on the Orchestration of Dynamic Localization
There are many possible mechanisms one might imagine initiating dynamic
localization that fit with the requirements described.
39,183
Here, we discuss our
two-part hypothesis detailing the orchestration of dynamic localization (
Fig. 4
).
Lesion (Abasic)
Damage Agent (ROS)
O
2
-
O
2
2 -
3
¢
5
¢
Superoxide
anion radical
Peroxide
OH
-
OH
H
2
O
2
5
¢
3
¢
Hydroxyl
radical
Hydrogen
peroxide
Hydroxyl
ion
Sensor
Protein
Oxidation
Redox sensor
Transducer
NODDS
/
MODDS
PTMs
Nuclear import
Nuclear export
Protein stability
Mitochondrial import
Nuclear export
Protein stability
F
IG
. 4. Proposed model for the transduction of nuclear oxidative DNA damage signals
(NODDS) and mitochondrial oxidative DNA damage signals (MODDS). The diagram shows two
potential pathways that could be responsible for the generation of NODDS and MODDS. The left
half shows how individual lesions (abasic sites) may be detected by sensor proteins and transduced
into NODDS and MODDS. The right half shows how DNA damage agents that induce the
formation of reactive oxygen species (ROS) may lead to protein oxidation of redox sensor proteins
and subsequent generation of NODDS and MODDS. The dashed arrow between the left and right
panels represents how signal transduction may occur through increasing ROS, potentially connect-
ing the two pathways. NODDS and MODDS lead to posttranslational modifications (PTMs) of base
excision repair (BER) proteins, ultimately causing an increase in either nuclear or mitochondrial
BER protein concentration through mechanisms described in the text.
