Biology Reference
In-Depth Information
phosphorylation of the DGs, UDG,
131,132
MYH,
133
and OGG1
134
has been
reported to modulate their repair function. Thus acetylation and phosphoryla-
tion of early BER/SSBR proteins play a key role in regulating their repair
functions and modulating their interactions with other repair proteins.
B. Ubiquitylation and BER Protein Turnover
Ubiquitylation has been demonstrated to play a role in regulating the
steady-state level of BER/SSBR enzymes in mammalian cells by directing
their degradation and turnover.
135
Ubiquitin is a highly conserved small protein
(
8.5 kDa) whose covalent addition to a target protein as a polymer by
ubiquitin ligases promotes the latter's degradation by the 26S proteasome.
136
However, ubiquitylated proteins may also be recycled by the removal of
ubiquitin by deubiquitylases (DUBs) or ubiquitin-specific proteases.
137,138
Proteins may be ubiquitylated with a single ubiquitin moiety (monoubiquityla-
tion) or with multiple ubiquitin molecules (polyubiquitylation). Pol
b
is ubiqui-
tylated by the E3 ubiquitin ligase Mule at Lys 41, 61, and 81, and substitution
of these Lys with Arg increased Pol
b
stability.
135
Furthermore, Mule-depleted
cells contain higher levels of Pol
b
and increased DNA repair activity. It was
recently demonstrated that APE1's ubiquitylation, which is enhanced by phos-
phorylation at Thr233,
139
could act as a signal for regulating the stability,
subcellular localization, and gene regulatory functions of APE1.
117,137
The
mammalian nuclear UDG, UNG2, is also ubiquitylated in cell. Blocking its
nuclear export using a nuclear export inhibitor prevents its ubiquitylation and
subsequent degradation.
140
This suggests that translocation of proteins from
the nucleus to the cytoplasm is required for their turnover. In a distinct situa-
tion, PCNA is both mono- and polyubiquitylated, thus mediating translesion
DNA synthesis and error-free lesion bypass, respectively.
141,142
V. BER/SSBR Deficiency in Human Diseases
Maintaining genomic integrity through DNA repair is essential for the
functioning and survival of an organism. Hence, defective or deficient repair
leading to accumulation of unrepaired genome damage has been associated
with a range of human disorders including cancer susceptibility, aging, and
various neurodegenerative diseases. While compelling evidence exists linking
deficiency in SSBR proteins to human diseases,
143
there is some controversy
regarding a similar association with the early BER proteins, presumably due to
the backup role of BER sub-pathways as discussed earlier.
