Biology Reference
In-Depth Information
mismatch repair (
Table I
).
98
For example, several human DNA glycosylases
have increased base excision activity in the presence of APEX1 (
Table I
).
98
Physical interactions also occur. For example, specific glycosylases associate
with X-ray repair cross-complementing group 1 (XRCC1) to enhance base
excision activity (
Table I
), while other BER proteins are known to interact
with proliferating cell nuclear antigen (PCNA) or replication protein A (RPA),
suggesting that DNA glycosylases are involved in postreplication BER
responses (
Table I
).
23,24,58,67,74
Known posttranslational modifications of BER proteins include phosphor-
ylation, acetylation, nitrosylation, ubiquitination, and sumoylation (
Table I
).
Phosphorylation of OGG1, A/G-specific adenine DNA glycosylase (MUTYH),
and UNG affects enzyme excision activity in different ways (
Table I
).
21,61,71
Acetylation by the histone acetyltransferase, p300, regulates OGG1, thymine
DNA glycosylase (TDG), endonuclease VIII-like 2 (NEIL2), polymerase beta
(pol
b
), and APEX1, each of them in a unique manner (
Table I
).
11
For instance,
acetylation of OGG1 causes a decrease in affinity for AP sites while increasing
both enzyme turnover and stimulation by APEX1. In contrast, acetylation of
NEIL2 significantly reduces both glycosylase and AP lyase activities.
56,63
Nitrosylation of BER proteins occurs for APEX1 and OGG1, in both cases
inhibiting repair activity, but doing so in different manners: triggering nuclear
export or inhibiting excision activity, respectively.
100,101,165
Ubiquitination of a
protein, which typically leads to degradation, is used as a method of controlling
steady-state protein levels, such as reported for Pol
b
.
166
Ubiquitination, how-
ever, can also have other roles such as with APEX1 ubiquitination which does
not affect protein degradation, but whose consequence is thus far unknown.
167
Lastly, sumoylation of a few BER proteins has been documented including
TDG, and the
S. cerevisiae
dual functional endonuclease III-like thymine
glycol DNA glycosylase/AP lyases (Ntg1) and (Ntg2).
39,168
The effect of TDG
sumoylation is best understood where the small ubiquitin-related modifier
(SUMO), competes with the regulatory domain of TDG for DNA binding,
allowing TDG to overcome product inhibition and ultimately increasing
enzyme turnover.
168,169
Protein localization is perhaps the most crucial form of regulation in
eukaryotic BER as BER proteins must be given access to the genomic DNA
in order to carry out their functions. As such, almost all BER proteins have
evolved a means for localizing to the nucleus, most via the classical nuclear
import pathway (
Table I
).
170
Classical nuclear import operates through the
recognition of a classical nuclear localization signal (NLS) by the NLS receptor,
importin
a
, which binds the NLS-containing cargo protein in the cytoplasm
and imports it into the nucleus through nuclear pores in complex with importin
b
.
171
Functional mitochondria are also important for cell survival and fitness,
making the maintenance of mitochondrial DNA by BER proteins critical.
172
