Biology Reference
In-Depth Information
BER proteins with known mechanisms of mitochondrial localization contain
mitochondrial matrix-targeting sequences (MTSs). These sequences are usu-
ally located at the N terminus of a protein and consist of 10-80 amino acids that
form amphipathic
a
-helices, which are recognized by the mitochondrial outer
membrane translocase.
173,174
Proteins with an MTS enter into the mitochon-
drial matrix after being passed from the outer membrane translocase to the
inner membrane translocase.
175-177
Protein localization may also be controlled
through protein-protein interactions and posttranslational modifications in
response to some stimuli, representing a higher level of protein localization
regulation.
178,179
C. Dynamic Localization
While none of the regulatory mechanisms mentioned above are responsible
for the regulation of each and every protein in the BER pathway, there are
some common threads that all BER proteins must share in order to effectively
maintain the genome. Foremost is the ability to localize to compartments
containing damaged DNA coupled with the ability to sense and play their
part in repairing damaged DNA in an efficient and accurate manner. As a
result, we believe the regulation of BER proteins is best carried out through a
combination of regulatory mechanisms with the end result being dynamic
localization of BER proteins.
Dynamic localization simply means that a protein can be mobilized to a
specific cellular compartment in response to environmental stimuli. There are
many examples of dynamic localization, including some proteins involved in
DNA repair (
Table II
).
39,180-188
The xeroderma pigmentosum, complementa-
tion group G (XPGC) protein relocalizes from the perinucleolar sites to the
nucleoplasm following UV irradiation, a process that requires a region of amino
acids containing one of the nuclear localization signals within XPGC.
187,189
The
E3 ubiquitin ligase (RAD18) protein localizes to double-strand breaks caused
by ionizing radiation independently of the cell cycle, but has differential cell
cycle-dependent localization, with RAD18 exhibiting nucleolar localization
during late G
2
before the G
2
/M transition.
182
Lastly, sumoylation is required
for localization of topoisomerase II to centromeres prior to anaphase, and in
the absence of this modification, nondisjunction may occur.
181
With respect to BER, dynamic localization is defined as the ability to sense
base damage and to recruit the appropriate enzymes and other proteins to
neutralize the threat to genome integrity of a compartmentalized genome.
Situations where dynamic localization of BER proteins is disrupted or inaccu-
rately activated could lead to mutagenesis and subsequent deleterious biolog-
ical consequences.
