Biology Reference
In-Depth Information
mitochondria acting as NODDS and MODDS. This response would be rapid,
in some cases occurring before or as DNA base lesions are forming, and would
be applicable to the recruitment of all of BER proteins.
A number of mechanisms could translate NODDS and MODDS into mo-
bilization of a protein to nuclei or mitochondria. There are two primary ways to
increase the nuclear concentrations of a fixed quantity of BER proteins. The first
is by increasing the rate of nuclear import, which can be achieved through
posttranslation modification of a number of targets. Posttranslation modification
of the BER protein itself could increase nuclear protein localization by creating a
new protein-protein interaction that allows for coimport to the nucleus; by
interfering with the mitochondrial MTS; or by enhancing the association for
receptors of the classical nuclear import pathway. Posttranslation modifications
could also occur on other proteins enhancing BER protein nuclear import. The
second method of increasing nuclear concentrations of BER protein is decreas-
ing nuclear protein loss, which may be achieved by reducing nuclear protein
export and/or by increasing nuclear protein stability through posttranslational
modifications on the BER proteins themselves and/or proteins involved in
nuclear export/protein degradation. Increasing mitochondrial concentrations
would occur in a similar manner but is likely limited to altering protein stability
and mitochondrial targeting as no known pathway exists to export proteins from
the mitochondria. A third possibility arises if we consider new protein synthesis
as a means to increase either nuclear or mitochondrial protein concentrations.
Transcriptional regulation may also occur in response to base damage as sensed
through abasic sites and might lead to increased nuclear and mitochondrial BER
protein levels. This mechanism would, however, be a slower response and would
not fall under the purview of dynamic localization.
Dynamic localization represents a novel mechanism for the regulation of
BER proteins, integrating many different levels of regulation into a consummate
solution flexible enough tomaintain both the nuclear and mitochondrial genomes
in ever-changing and complex environments. Understanding the underlying
pathway driving dynamic localization and the extent to which this regulatory
mechanism coordinates BER repair in humans is critical given hints that the
process may have roles in cancer and other neurodegenerative disorders.
References
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2. Nakamura J, Swenberg JA. Endogenous apurinic/apyrimidinic sites in genomic DNA of
mammalian tissues.
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3. Ferguson LR. Chronic inflammation and mutagenesis.
Mutat Res
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