Biology Reference
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binding with YB-1 both
in vivo
and
in vitro
,
80
leading to the activation of the
multidrug resistance (
MDR1
) gene. Thus, it appears likely that acetylation-
mediated conformational change in the disordered N-terminal segment (
40
residues), which is dispensable for APE1's endonuclease activity, modulates
protein-protein interactions. The physiological importance of APE1 acetyla-
tion became more evident with our findings that the levels of acetylated APE1
are increased in response to a variety of cellular stresses, or changes in
intracellular Ca
2
รพ
, or bacterial infection to gastric epithelial cells.
120,121
We
also showed that hNEIL2 is acetylated at Lys49 and Lys153 both
in vitro
and in
cells.
122
Acetylation of Lys49 located in the disordered region inactivated
NEIL2's base excision and AP lyase activity while acetylation of Lys150 had
no effect. We thus proposed that acetylation of Lys49 could act as a regulatory
switch in NEIL2.
122
TDG is acetylated at Lys70, 94, 95, and 98 in the
N-terminal region, within the disordered segment (
100 residues).
123
Acety-
lation of TDG by CBP/p300 indirectly deregulates TDG-coupled repair by
releasing CBP/p300 from the DNA-bound complex, leading to reduced inter-
action with APE1 and suppressing APE1-dependent repair, and could contrib-
ute to genomic instability,
123
Acetylation of hOGG1 occurs at Lys338 and Lys341 within its short
disordered C terminus, and the modification increases OGG1's turnover by
reducing its affinity for the product AP site.
124
Moreover, oxidative stress
increases the level of acetylated OGG1, most likely as a result of ROS-induced
activation of p300. We have speculated that OGG1 acetylation provides a
mechanism for rapid cellular response without requiring its de novo synthesis
when enhanced repair is promptly needed for handling increased lesion load in
cell genomes after exposure to oxidative stress. This is further supported by our
observation that the repair of 8-oxoG is correlated with the level of acetylated
OGG1.
124
APE1 was also shown to be phosphorylated
in vitro
and in cells by protein
kinase C.
117,125,126
APE1 can also be phosphorylated
in vitro
by casein kinase I
and II (CKI and CKII) at various sites
126,127
; CKII-mediated phosphorylation
abolished DNA repair activity
in vitro
, while phosphorylation by CKI or PKC
had no such effect.
126
APE1 phosphorylation by CKII also enhances transacti-
vation of the AP-1 transcription factor.
128
XRCC1 in human cells is phosphor-
ylated by CKII and is required for its stability and efficient BER/SSBR.
129
More recently, Huang
et al.
found that APE1 was phosphorylated at its Thr233
residue by threonine kinase CDK5, a paralog of CDK2/4.
130
CDK5 is
expressed in neurons and is speculated to be involved in cell death triggered
by uncontrolled DNA replication. A high level of phosphorylated Thr233 was
observed in brain tissues from Parkinson's and Alzheimer's patients,
130
and
inactivation and degradation of APE1 by phosphorylation and the subsequent
ubiquitylation may profoundly affect the severity of the diseases. Furthermore,
