Biology Reference
In-Depth Information
First, we hypothesize that dynamic localization is initiated through sensing
either base damage or DNA-damaging agents, which results in the generation
of nuclear oxidative DNA damage signals (NODDS) or mitochondrial oxidative
DNA damage signals (MODDS). Second, NODDS and MODDS lead to an
increase in nuclear or mitochondrial BER protein levels, respectively.
There are a finite number of ways in which a cell can detect DNA base
damage: the lesions themselves repair intermediate lesions, or released damage
products. Detection of strand breaks, the most dangerous lesions to a cell,
operates by sensing the lesions themselves: double-strand breaks are detected
by the MRN complex (comprised of Mre11, Rad50, and Nbs1), which leads to
ATM kinase pathway signaling, while single-stranded DNA (an extended
single-strand break) is recognized by RPA, leading to ATR kinase pathway
signaling.
215,216
Direct sensing of DNA lesions is a common theme in DNA
damage signaling, so if a signaling mechanism for BER-repairable damage
exists, as is suggested by the dynamic localization of Ntg1, the base lesions
themselves are candidates for the proximate DNA base damage signal. We
propose that of the base lesions repaired by BER, abasic sites (intact, 3
0
-, or 5
0
-
cleaved) are responsible for creating NODDS and MODDS and initiating
dynamic localization of BER proteins. Abasic sites are uniquely suited to a
general signaling role for BER as all base lesions repaired by BER have an
abasic site as an intermediate.
6
Furthermore, all cellular compartments contain
a basal level of their set of glycosylases, allowing an abasic site to be quickly
generated from the initial base lesion.
7
Each abasic site sensed by the cell
would lead to the generation of an oxidative DNA damage signal, which would
then recruit BER proteins to the appropriate organelle.
Dynamic localization may also be driven through organellar detection of
the threats responsible for causing DNA base lesions themselves. Agents that
cause DNA base damage such as ROS and alkylating agents also react with
other cellular products like proteins. Posttranslational modification of key pro-
teins by these DNA-damaging agents may be the cause of BER protein
dynamic localization. ROS are uniquely suited to fill this role because of the
existence of complex mechanisms for controlling cellular ROS levels and
because of their roles in signaling to redox sensor proteins.
217,218
An alternative
hypothesis to the one presented is that DNA-damaging agents themselves
functioning through redox-sensing proteins are responsible for creating
NODDS and MODDS, initiating dynamic localization of BER proteins.
There are many examples of posttranslational modifications of protein by
ROS, driving changes in activity, abundance, localization, and interaction
with other proteins.
218
Furthermore, nonoxidative DNA-damaging agents in-
duce an increase in ROS, allowing for many types of base damage to trigger
redox signaling in this manner.
219
Redox sensor proteins would initiate dynamic
localization of BER proteins by sensing ROS levels in either the nuclei or
