Biology Reference
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ubiquitination, sumoylation, and even palmitoylation (though the last men-
tioned is probably an anomaly). Some of these modifications are predicted to
occur within or adjacent to the localization sequences and may play a role in
altering protein localization. Most of these modification sites have not yet been
experimentally verified but have the potential to play any number of roles in
regulating the activity of these proteins, including, but not limited to, the
alteration of protein localization by interfering with localization sequences or
creating new protein interfaces; enzyme specificity for AP sites; or substrate
turnover rates. Sumoylation of Ntg1 has been confirmed, as will be discussed
later, and phosphorylation of Mag1 and Apn1 by various kinases, including
those involved in DNA damage signaling, has been observed in a number of
high-throughput screens. 212-214 The human homolog NTHL1, like Ntg1, con-
tains both an NLS and an MTS, and an iron-sulfur center like Ntg2. 51 NTHL1
is relatively unique among human BER proteins in having a single isoform with
both localization signals. The human UNG has dedicated nuclear and mito-
chondrial isoforms. Still others, like nudix (nucleoside diphosphate linked
moiety X)-type motif 1 (NUDT1), OGG1, and MUTYH, are more complex;
some of their multiple isoforms have only an MTS, some only have an NLS, and
some have both. 69
D. Insight into Dynamic Localization
Through the study of Ntg1, insight has been gained as to how dynamic
localization may result through the targeting of Ntg1 to the nucleus in response
to DNA damage. Ntg1 requires a classical nuclear localization signal to localize
to the nucleus in response to DNA damage; the importance of nuclear local-
ization also extends beyond the NLS to include the requirement that the
classical nuclear import pathway remain intact. 183 These requirements suggest
that classical nuclear import is the means by which proteins are targeted for
nuclear dynamic localization and not some other alternative import pathway,
signifying that the classical nuclear import pathway is a key regulator of
genomic stability. A possible missing link between the DNA damage signal
and a change in protein localization could be the posttranslational modification
of Ntg1 by the SUMO. 39 Sumoylated Ntg1 is likely restricted to the nuclear
compartment with no sumoylated Ntg1 detected in the mitochondria; in fact,
the nuclear level of sumoylated Ntg1 increases fivefold upon treatment of cells
with hydrogen peroxide. 39 This change in Ntg1 status suggests a potential
mechanism for how Ntg1 may be targeted to the nucleus with Ntg1 sumoyla-
tion targeting Ntg1 to or sequestering Ntg1 within the nucleus in response to
nuclear oxidative DNA damage.
What event drives Ntg1 to the mitochondria in response to mitochondrial
DNA damage remains unclear. However, if Ntg1 is not able to dynamically
localize to the mitochondria or to the nucleus, spontaneous mutation rates
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