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have the capacity to localize to more than one cellular compartment containing
damaged DNA. In eukaryotic cells, BER proteins must thus be capable of dual
localization to both the nucleus and the mitochondria. Localization to the
nucleus for many BER proteins relies on the classical nuclear import path-
way. 183 This pathway may be critical for dynamically targeting BER proteins to
the nucleus as in one instance, when the NLS of a protein is abolished, the
ability to respond to nuclear DNA damage is lost. 170 Mitochondrial localization
follows the same pattern with both basal and dynamic mitochondrial localiza-
tion relying upon the MTS. 183 The details of translating the initial signal into a
change in localization are as yet unknown; however, it would involve a mech-
anism utilizing standard targeting signals ( Fig. 2 ).
C. Examples of Dynamic Localization in Response to
Genotoxic Stress
To date, the best characterized example of dynamic localization in response
to DNA damage is the S. cerevisiae dual functional glycosylase/AP lyase,
Ntg1. 39,183 Ntg1 possesses all the basic components required for dynamic
localization including a bipartite classical nuclear localization signal and a
mitochondrial MTS. 183 Dynamic localization of Ntg1 changes the basal local-
ization of Ntg1 from both nuclei and mitochondria to a primarily nuclear
localization in response to nuclear oxidative and alkylation stress, and to a
more mitochondrial localization in response to mitochondrial oxidative stress. 39
Like budding yeast Ntg1, the human ortholog of Ntg1, NTHL1, has all the
necessary components to respond to organelle-specific DNA damage signals as
it contains both a classical nuclear import signal and a mitochondrial MTS. This
aspect of NTHL1, however, has yet to be examined.
Another repair protein which dynamically localizes is the human Cockayne
syndrome complementation group B (CSB) protein. 180 CSB has a role in
transcription coupled repair (TCR), which is initiated when RNA polymerase
II progression is blocked by DNA damage in the transcribed strand, triggering
recruitment of NER proteins. 190 CSB, however, also operates outside of TCR
and may have roles in the BER pathway in nuclei and mitochondria because
CSB interacts with poly (ADP-ribose) polymerase (PARP1), APEX1, and
endonuclease VIII-like 1 (NEIL1), and because CSB-deficient cells accumu-
late oxidative DNA damage. 191-194 Dynamic localization of CSB increases
mitochondrial localization of CSB in response to mitochondrial oxidative stress
where CSB affects incision activity of mitochondrial extracts for oxidative base
damage. 180 This work reveals that dynamic localization is an important mech-
anism for the regulation of BER in humans and underlines the importance of
understanding this process further.
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