ANTIOXIDANTS & REDOX SIGNALING

Volume 20, Number 4, 2014

Mary Ann Liebert, Inc.
DOI: 10.1089/ars.2013.5736

FORUM EDITORIAL

DNA Repair Meets the RNA World

Chow H. Lee

Abstract

The ability to repair damaged DNA and to maintain genome stability is the utmost importance for the survival of any
species. Hence, it is not surprising to find that DNA repair mechanisms are evolutionarily conserved and are expected
to evolve to maintain the existence of species. In the last few years, there has been an exponential increase in the
evidence linking RNA processing with DNA repair programs. For instance, the well-studied DNA base excision
repair (BER) enzyme apurinic/apyrimidinic endonuclease 1 can cleave RNA molecules, regulate mRNA levels, and
associate physically with proteins involved in RNA processing. It is now clear that not only the expression of
noncoding RNAs are changed upon DNA damage, they can modulate the expression of genes involved in the genome
stability programs. The five reviews in this Forum provide the up-to-date knowledge on DNA repair, with a focus on
BER, and a perspective on how the two ancient biochemical pathways are linked. The contributions demonstrate the
complexity of such interactions, but also pointed out the opportunities for new therapeutic interventions. Future
in vivo studies on the link between DNA repair processes and RNA metabolism should contribute to our basic
understanding of physiology, disease, and treatment strategies. Antioxid. Redox Signal. 20, 618620.

Introduction

henever I teach my undergraduate students topics in

nucleic acids, I often stress the differences between
DNA and RNA molecules. RNA is made of uracil instead of
thymine in DNA and which has an additional methyl group at
its C5 position of the base and therefore thymine is sometime
known as 5-methyl uracil. In addition, RNA has a hydroxyl
group at C2 position of its sugar molecule, whereas the
sugar moiety in DNA lacks such hydroxyl groups. Such
subtle differences contribute to the differences in the
chemistry and structure of DNA and RNA. Based on information in the textbook, we also teach students that there
are specific enzymes and proteins involved in DNA metabolism such as DNA repair, and then, there are other
specific enzymes and proteins involved in RNA metabolism. Findings in the last few years on the enzymes and
pathways of DNA repair have now confirmed that this is not
the case. The processes of DNA repair and RNA metabolism
are more intimate than we previously thought. Two recent
reviews have dealt on specific topics in this field (5, 7). This
Forum aims to provide up-to-date information in the field of
DNA repair, particularly on base excision repair (BER), and
a perspective on how DNA repair mechanism and RNA

metabolism, the two ancient biochemical pathways, are

linked (Fig. 1).
Oxidative Damage and BER

First, the review by Scott et al. (6) provides an overview of

the DNA repair pathways. The role of reactive oxygen species in DNA damage and its link to cancer formation was
nicely discussed. The review then focuses on the BER
pathway, providing a historical look at the development of
the field, and then, the detailed steps in BER with the most
updated information. The most studied base damage 8hydroxyguanine and the enzymes responsible for its repair
were also discussed. Finally, Scott et al. (6) briefly discussed
one of the most studied BER enzymes, apurinic/apyrimidinic
endonuclease 1 (APE1). APE1s multiple activities, subcellular localization, and links with cancer were summarized,
which very nicely take us into the next review, which is
entirely devoted to this very important enzyme.
The Human APE1

Li and Wilson (3) provide a comprehensive review and

recent findings on the human APE1. A short history on the

Chemistry Program, University of Northern British Columbia, Prince George, Canada.

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DNA REPAIR MEETS THE RNA WORLD

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FIG. 1. The link between DNA

repair and RNA metabolism. The
schematic diagram provides an
overview on how components in
the DNA repair and RNA metabolism are bridged as referred to in
the Forum contributions. The critical issues are whether these interactions have implications for our
understanding on the physiology,
pathology, and disease treatment
strategies. To see this illustration in
color, the reader is referred to the
web version of this article at www
.liebertpub.com/ars

discovery of the enzyme, its sequence, and structural similarities to its orthologues, including Exonuclease III from
Escherichia coli, were presented. The authors discuss all the
known biochemical activities of APE1, including its most
recently discovered ability to cleave RNA species. Evidence
for the various significant biological roles of APE1, including
those in the cytoplasm and mitochondria, was also discussed.
The review then describes the possible link between APE1
and human diseases such as cancer and neurological diseases,
focusing on the possible contribution of APE1 variants. Finally, Li and Wilson (3) discuss the current and future
strategies in targeting APE1 for therapeutic purposes. Interestingly, another BER enzyme SMUG1 has recently
been shown to cleave single-stranded RNA and physically
associate with DKC1, a ribosomal RNA processing protein (2). More surprisingly, the SMUG1/DKC1 interaction
targets the complex to nucleoli contributing to ribosomal
RNA quality control (2), a feat that is remarkably similar to
APE1 (1).
Roles of the Nucleolus in DNA Damage Response

The review by Antonialli et al. (1) discusses the evidence

for the roles of the nucleolus in regulating DNA damage
response (DDR). The authors first provide an overview on
RNA oxidative damages followed by description of the
structure, composition, and known functions of the nucleolus,
namely, in the processing of ribosomal RNAs. It is proposed
that some proteins contain nucleolar localization sequences,
and the nucleolus serves as a storage organelle for many
nuclear proteins, including proteins involved in DNA repair.
The authors discuss the interaction between APE1 and the
hub protein in the nucleolus, nucleophosmin, as an example
whereby the nucleolus may serve as a hub for the repair of
oxidatively damaged RNA upon stress. Last, it is proposed
that some proteins evolve to possess an unfolded protein

domain such as those found at the N-terminus of APE1. The

authors discuss that such domain is important for biomolecular interactions and could serve as a novel target for therapeutic purposes.
Post-Transcriptional Regulation of DDR

The review by McKay (4) describes the significant role

played by mRNA stability in the regulation of DDR. McKay
first discusses the evidence that, ultraviolet light can lead to
inhibition of the synthesis and processing of transcripts. The
review briefly describes the many cellular pathways activated upon DNA damage, including the p53-dependent and
-independent transcriptional mechanisms. McKay then discusses the significance of the mRNA stability pathway in
circumventing the transcriptional inhibition imposed upon
DNA damage. Several p53-responsive mRNAs contain sequences at their 3-untranslated region that can destabilize
their transcripts, supporting the evidence that transcription
and mRNA stability regulation are closely linked. The review
also discusses the evidence that ultraviolet light can lead to
increased stability of mRNAs as well as accelerated decay of
other sets of mRNAs.
Noncoding RNAs in DNA Repair

Finally, the review by Wan et al. (8) discusses the

emerging roles of noncoding RNAs (ncRNAs) in DNA repair
and genome integrity. The authors provided many examples
of microRNAs and long ncRNAs regulating the key genes in
DDR and reactive oxygen species signaling pathways. The
review also discusses the potential roles of other small
ncRNAs in regulating DDR. In addition, the expression
profiles of ncRNAs are itself modulated upon DNA damage.
The authors discuss the evidence that both the transcriptional
and post-transcriptional mechanisms of ncRNAs are modulated. Wan et al. (8) propose and discuss that ncRNAs

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involved in the DDR could serve as diagnostic biomarkers

and therapeutic targets.
Summary

This Forum illustrates the progress and critical issues in

our understanding of DNA repair mechanisms, particularly
on the BER pathway. The discovery of DNA repair proteins
such as APE1 and SMUG1 to have a role in RNA metabolism
and the increasing evidence for the role of ncRNAs in the
regulation of DNA repair processes have added the unexpected complexities, but at the same time offer unique opportunities for new therapeutic intervention. I believe that in
the near future, there will be more surprising findings, which
will reveal the unexpected link between DNA repair mechanisms and RNA metabolism. Would such an understanding
at the molecular level lead to new insights into physiology,
disease, and treatment strategies? These are the challenging
questions that need to be addressed.
Acknowledgment

The author thanks the Natural Sciences and Engineering

Research Council (#227158) for their continuous financial
support.
References

1. Antonialli G, Lirussi L, Poletto M, and Tell G. Emerging

roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1
as a paradigmatical example. Antioxid Redox Signal 20:
621639, 2014.
2. Jobert L, Skjeldam HK, Dalhus B, Galashevskaya A, Vagbo
CB, Bjoras M, and Nilsen H. The human base excision repair
enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control. Mol Cell 49: 330345, 2013.
3. Li M and Wilson DM III. Human apurinic/apyrimidinic
endonuclease 1. Antioxid Redox Signal 20: 678707, 2014.

LEE

4. McKay BC. Post-transcriptional regulation of DNA damageresponsive gene expression. Antioxid Redox Signal 20: 640
654, 2014.
5. Montecucco A and Biamonti G. Pre-mRNA processing
factors meet the DNA damage response. Front Genet 4: 102,
2013.
6. Scott TL, Rangaswamy S, Wicker CA, and Izumi T. Repair
of oxidative DNA damage and cancer: recent progress in
DNA base excision repair. Antioxid Redox Signal 20: 708
726, 2014.
7. Sharma V and Misteli T. Non-coding RNAs in DNA damage
and repair. FEBS Lett 587: 18321839, 2013.
8. Wan G, Liu Y, Han C, Zhang X, and Lu X. Noncoding
RNAs in DNA repair and genome integrity. Antioxid Redox
Signal 20: 655677, 2014.

Address correspondence to:

Dr. Chow H. Lee
Chemistry Program
University of Northern British Columbia
3333 University Way
Prince George, BC V2N 4Z9
Canada
E-mail: chow.lee@unbc.ca
Date of first submission to ARS Central, November 6, 2013;
date of acceptance, November 18, 2013.
Abbreviations Used
APE1 apurinic/apyrimidinic endonuclease 1
BER base excision repair
DDR DNA damage response
DKC1 dyskerin
ncRNA noncoding RNA
SMUG1 single-strand-selective monofunctional
uracil-DNA glycosylase 1