Biology Reference
In-Depth Information
Our initial discovery that OGG1 and NTH1 are active only with the duplex
DNA while NEILs are more active with ss DNA substrates that mimic replicat-
ing or transcribing sequences led us to hypothesize that NEILs preferentially
function in repair during DNA replication and/or transcription.
66
We subse-
quently characterized the role of NEIL2 in preferential repair of transcribed
genes, where NEIL2 functionally interacts with RNA polymerase II.
74
Unlike
NEIL2, NEIL1 is induced in S-phase cells and functionally interacts with
DNA replication proteins including PCNA, replication protein A (RPA)
FEN-1, and Werner's helicase (WRN), which suggests that NEIL1 is prefer-
entially involved in replication-coordinated BER.
33,34,75-78
B. Role of Noncanonical Proteins
Several noncanonical proteins have been shown to be involved in BER,
adding another dimension to the BER complexity. However, their precise
in vivo
functions in BER/SSBR are yet to be unraveled. We showed that
NEIL2 interacts with YB-1, a Y-box binding protein, and it was suggested
that YB-1 may be required for the fine-tuning of repair.
79
NTH1 and APE1
were also shown to interact with, and be stimulated by, YB-1.
80,81
Recently,
Banerjee
et al.
showed association of NEIL2 with hnRNP-U, an RNA-binding
protein, and its role in transcription-coupled BER.
74
HMGB1 has been impli-
cated in SSBR involving Pol
b
.
82
Tumor suppressor protein p53 interacts with
APE1 and Pol
b
, and stimulates BER
in vitro
.
83
P53 was also shown to play a
role in UV radiation-induced DNA damage repair.
84
Jaiswal
et al.
showed
inhibition of both SN-BER and LP-BER or LP-BER alone by the adenoma-
tous polyposis coli (APC) and by cyclin-dependent kinase inhibitor p21 genes,
respectively.
85,86
The growing list of noncanonical proteins underscores the
paradigm that BER/SSBR
in vivo
is far more complex than
in vitro
repair
demonstrated with minimal components.
C. Repair Interactome: Preformed Complexes Versus
Sequential Recruitment
The prevailing view of BER is that it comprises a sequence of steps with
individual repair enzymes carrying out reactions independently of one another.
This concept was initially proposed based on X-ray crystallographic studies, as a
''hand-off'' or ''passing the baton'' process, wherein the repair product of each
enzyme in the BER pathway is handed over to the next enzyme, primarily based
on differential bending of DNA in each intermediate step.
35,87,88
However, our
recent studies as well as others' have shown that early BER/SSBR enzymes (e.g.,
NEIL1, APE1) stably interact with most downstream repair components in-
cluding DNA ligase, via their common interacting domain.
11,32,77,78,89
Further-
more, NEIL1 and NEIL2 immunoprecipitates (IP) from human cells contain
