Biology Reference
In-Depth Information
and colleagues identified the presence of nCaRE
sequences on the promoter of
APE1
gene itself, demon-
strating that APE1 could downregulate its own gene
and this negative feedback mechanism would represent
the first example of such a transcriptional self-
regulatory mechanisms for a DNA repair enzyme.
154
However, experimental results show that APE1 is not
able to directly bind nCaRE elements, requiring the
presence of other protein factors like the heterogeneous
ribonucleoprotein-L (hnRNP-L).
75
More recently, it has
been demonstrated that increased extracellular calcium
concentration can induce p300-dependent acetylation of
APE1 at the level of lysine residues 6 and 7, increasing
APE1 binding capability on nCaRE elements.
155
The
discovery of calcium-induced APE1 acetylation and its
effect on DNA binding activity suggested that specific
post-translational modifications may provide a means
for regulating this multi-functional protein's different
activities.
Regulation of APE1 Functions
APE1 is a multifunctional protein that exerts several
different and in some ways antithetic functions within
the cell. APE1 activities are correlated with cell survival
mechanisms, but at the same time with proapoptotic
pathways. Due to the peculiar nature of this protein,
all its functions must be fine-tuned. At least three
different levels of regulation exist: transcriptional, sub-
cellular localization and post-translational modification
(PTM). As already mentioned, APE1 exerts an inhibitory
effect on its own expression in response to intracellular
calcium levels, by binding nCaRE sequences present
on its promoter.
154
In addition, mechanisms of
APE1
inducible activation in response to oxidative stress and
hormones, such as TSH, are well documented.
162
Sub-
toxic doses of ROS strongly increase APE1 mRNA levels
in different cell lines.
163
Remarkably, after induction of
APE1 expression cells are rendered more resistant to
a second insult with H
2
O
2
, due to APE1 increased
levels.
164
Nevertheless, the correlation between this
adaptive response to cellular oxidative stress and ROS-
induced expression of APE1 are still not completely
understood.
PTM of a protein represents a quick and in some
cases, reversible way to modulate proteins' different
activities. As of today, five different kinds of PTM of
APE1 have been described occurring
in vivo
and affect
APE1 function and localization: acetylation, phosphory-
lation, ubiquitination, S-nitrosation, and the proteolytic
removal of N33-terminal portion.
165
A more detailed
discussion of critical PTM on APE1 can be found in
Busso
et al.
's review.
166
Acetylation of APE1 lysine residues 6 and 7 in
response to intracellular Ca
2
รพ
levels increases its
binding capability on nCaRE elements.
155
Very recently,
acetylation of lysine residues 27, 31, 32, 35 have also
been demonstrated occurring
in vivo
and appear to stim-
ulate APE1's catalytic activity on AP site-containing
dsDNA.
167
These lysine residues are essential to APE1
interaction with nucleophosmin (NPM1) and RNA,
and therefore acetylation could possibly redirect a func-
tionally active form of APE1 from a buffering storage
site, such as nucleoli, toward active sites of DNA repair.
Contrasting data about APE1 phosphorylation and
the role of this modification in controlling its activities
were reported in literature: Yacoub and colleagues docu-
mented that APE1 was phosphorylated by casein kinase
II (CKII) and that the modification inactivated its endo-
nuclease activity.
168
However, another group reported
APE1 phosphorylation by CKII to be responsible for
an enhanced redox activity but without any effect on
its DNA repair function.
169
Computational analysis of
APE1 sequence highlighted the presence of CKI, CKII,
GSK3,
APE1 Role in RNA Metabolism
Back in 1995, Barzilay and colleagues hypothesized
for the first time the involvement of APE1 in RNAmetab-
olism, demonstrating its RNase H activity.
156
Later on, it
has been suggested that APE1 could also bind to RNA
molecules
in vivo
, being associated with ribosomes in
the cytoplasm of different cell types.
138
Besides the direct
interaction with RNAmolecules, APE1 was also found to
be able to interact with other protein factors involved in
RNA metabolism such as YB-1
157
and hnRNP-L.
75
All
these observations suggested a direct involvement of
APE1 in RNA metabolism, but until recently it was not
clear which kind of activity APE1 could exert on RNA
molecules. Marenstein and colleagues first demonstrated
that APE1 is able to exert its endonuclease activity not
only on AP-sites containing dsDNA but also on ssDNA
molecules.
158
Then, the same activity of APE1 was
described on an abasic ssRNA molecule, underlining
the relevance of the substrate conformation rather than
the nucleotide sequence.
159
In comparison to genomic
DNA, RNA molecules are mostly single-stranded, with
the bases not protected by hydrogen bonding or binding
to specific proteins. These features result in more suscep-
tibility to oxidative insults than DNA. If not repaired,
damage to RNAs could cause altered pairing leading to
ribosomal dysfunctions and an erroneous translation
process, thus significantly affecting the overall protein
synthesis mechanism.
160
Oxidative damage to RNA
molecules, both coding for proteins (mRNA) or perform-
ing translation (rRNA and tRNA), has recently been
associated with the occurrence of neurodegenerative
diseases such as Alzheimer's disease
161
and its impact
in cancer development cannot be excluded at present.
159
and PKC consensus
sites, but only the
