Table Of ContentD NA Recombination and Repair
F r o n t i e rs in M o l e c u l ar Biology
SERIES EDITORS
B. D. Hames D. M. Glover
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TITLES IN THE SERIES
1. Human Retroviruses 12. Eukaryotic Gene Transcription
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2. Steroid Hormone Action 13. Molecular Biology of Parasitic Protozoa
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3. Mechanisms of Protein Folding 14. Molecular Genetics of Photosynthesis
Roger H Pant Bettif A Hugh Sailer, ¡atue< Harbor
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4. Molecular Glycobiology 15. Eukaryotic UNA Replication
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16. Protein Targeting
5. Protein Kinases
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17. Eukaryotic mRNA Processing
6. RNA-Protein Interactions
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18. Genomic Imprinting
7. DNA-Protein: Structural Interactions
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19. Oncogenes and Tumour Suppressors
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8. Mobile Genetic Element»»
20. Dynamics of Cell Divisi
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9. Chromalin Structure and Gene Expression
Sarah C. K H^ta 21. Prokaryotic Gene Expression
10. Cell Cycle Control
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22. DNA Recombination and Repair
11. Molecular Immunology (Second Edition)
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D NA R e c o m b i n a t i on
and Repair
EDITED BY
Paul J. Smith and Christopher J. Jones
Department of Pathology
University of Wales College of Medicine
Cardiff Wales
OXFORD
U N I V E R S I TY PRESS
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A catalogue record for this book is available from the British Library
library of Congress Cataloging in Publication Data
DNA recombination and repair/edited by Paul J. Smith and Christopher
J. Jones.
(Frontiers in molecular biology; 22)
Includes bibliographical references and index.
1. DNA repair. 2. Genetic recombination. I. Smith. Paul J.
(Paul James), 1953-. II. Jones. Christopher J. (Christopher
John). 1965-, III. Series.
QH467.D156 1999 572.86459—dc21 99-32315
ISBN 0-19- 963707- 5 (Hbk)
ISBN 0-19-963706-7 I Pbk)
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Preface
All organisms whether of single or multicellular origin invest in the preservation of
the integrity of their genetic material. For a number of years there was a tacit
acceptance by the wider scientific community that there must be mechanisms in
place to maintain genomic stability. Furthermore, there was an expectation that
studying cells under stress, particularly after the induction of DNA damage, would
help to uncover the cellular tactics involved. However, many researchers were dis
mayed by the lack of information on the underlying processes which could support
such mechanisms and the need to describe pathways in nebulous terms. The
discovery of the significant overlap of DNA repair mechanisms and basic cellular
transactions such as DNA replication and basal transcription gave the field new
impetus. The journal Science recognized years of careful and patient research when
awarding DNA repair the rather cumbersome title 'Molecule of the Year' in 1994.
With the identification of repair genes and characterization of their biochemical
activities it is becoming increasingly apparent that lesion handling strategies lie at
the heart of the cell's integrated response to a variety of stresses.
No short book can address the myriad of issues that have projected the cellular
processes of DNA repair and recombination to centre stage for so many researchers
working in what were originally thought to be disparate fields. This publication has
attempted to highlight a selection of some of the issues currently at the frontiers of
our understanding of these processes.
Although repair was originally viewed as a process that prevented the 'fixation' of
DNA lesions, limiting chromosome ¿aberrations and mutation, it is now realistic to
view DNA repair as only one facet of the cellular response to DNA damage. As such
repair must be integrated with other pathways to effect physiologically and genetic
ally satisfactory outcomes for the individual cell, affected tissue system, and organ
ism. It is becoming increasingly clear that the fidelity of these integrated responses is
affected by the accrual of some of the genetic lesions that constitute the multistep
progression typical of neopiasia. The cancer predisposition disorders offer various
insights into the consequences of the dysfunction of integration. Thus at many points
the chapter authors have touched upon the relevance of DNA repair and recombina
tion for human ill health, in particular cancer.
Integration of DNA repair with other cellular processes has occurred throughout
evolution, linking pathways for stress signalling, adaptive responses, recombination,
recovery mechanisms, cell-cycle delay, transcription and replication, and not least
the molecular guillotine of programmed cell death, apoptosis. Although clearly im
portant to the resolution of stress responses in normal and tumour tissues, the
molecular pathways for apoptosis induction are not formally considered in this book
but are clearly referenced where appropriate.
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vi PREFACE
The book starts with the vital issue of DNA structure and folding dynamics, which
eventually all processes involving protein-DNA interactions must address. David
Leach's introductory chapter on molecular processing of DNA folding anomalies in
Eschcrichii) coii explores the consequences of different DNA structures and repeat
sequence modification, leading to a discussion on the inhibition of DNA replication
and initiation of homologous recombination by SbcCD protein. Developing the
relationships between double-strand break repair and V(D)J recombination the
chapter by Belinda Singleton and Penny Jeggo considers how the important features
of recognition and cleavage of signal sequences impact upon double-strand break
repair, with implications for homologous recombination and non-homologous end-
joining.
The following two chapters consider different strategies for dealing with DNA
lesions or mismatches. The ability of £. col i and yeast cells to enact translesion
replication, 'usually a strategy of last resort' is examined in detail in the chapter by
Christopher Lawrence and Roger Woodgate, with speculations on translesion repli
cation in humans. Bacterial mismatch repair is briefly discussed in the chapter by
Peter Karran and Margherita Bignami. The dramatic role of mismatch repair in
human cancers is dealt with in more detail together with an important overview of
areas ripe for the future study, such as the linkages between mismatch repair,
transcription-coupled excision repair and recombinational repair. Again this chapter
echoes the need to view the responses to DNA damage as an integrated response
with a discussion of mismatch repair, cell-cycle checkpoints, and apoptosis.
One of the great success stories in DNA repair research, resulting from the tenacious
work of many groups, has been the elucidation of much of the enzymology of
excision repair. An excellent chapter by Hanspeter Naegeli explores the complex
enzymology of human nucleotide excision repair, highlighting the substrate dis
crimination problem and potential sensors. This discovery, now a paradigm for the
selective repair of DNA lesions for biological advantage, is discussed in an overview
of transcription-coupled repair and global genome repair in yeast and h u m a ns by
Marcel Tijsterman, Richard Verhage, and jaap Brouwer. The authors have also ex
plored the connection between nucleotide excision repair and other repair pathways
such as mismatch repair. Along with xeroderma pigmentosum, the rare cancer-
prone disorder ataxia-telangiectasia has acted to reveal the complexity of the re
sponses of human cells to DNA damage, and the chapter by Martin Lavin and Kum
Kum Khanna details the nature of the ATM protein and gene family. The ATM story
has, perhaps more than any other, served to reveal the multiple levels at which stress
responses integrate with proliferation control.
The final chapter by Paul Smith and Chris Jones takes up the theme of the integra
tion of DNA repair into other cellular pathways by viewing the field primarily from
the perspective of the tumour suppressor gene product p53. In doing so this chapter
echoes themes developed in other chapters, including a perspective on cancer
predisposition in the general population. In particular, the overview touches upon
the induction, processing, and repair of DNA damage and the integration of these
events with proliferation control. One area addressed is the spectrum of unusual
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PREFACE vi i
forms of DNA damage induced by anticancer agents and the consequences for DNA
repair and drug resistance, since an expanding area of anticancer research involves
the identification of specific repair inhibitors. Importantly, the 'physiological' role of
endogenous damage induction, as a programmed route for the development of
senescence barriers to continuous cell proliferation, is highlighted through the events
controlling telomere dynamics.
We thank the authors for responding to our initial suggestions with vigour, and
expanding upon the themes in a manner that reflects the exciting nature of research
in this field, and connects with subjects addressed in other publications in the
'Frontier*' series.
Cardiff PJ.S
August 1999
CJ.J
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Contents
List of contributors
XV
\bbreviatiotis # »
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1 Molecular processing of DNA folding anomalies in
1
D A V ID R F I P A TH
1. Introduction
1
2. Folding anomalies in DNA
1
2.1 Hairpin DNA
I
2.2 Pseudo-hairpin DNA and S-DNA
2.3 H-DNA *H-DNA, and nodule DNA
4
;-PNA
h.
2.5 Quadruplex DNA
h
3. Deletions at direct repeats stimulated by closely spaced inverted
repeats
b
4. Duplications and i n v e r s i o ns stimulated by closely spaced inverted
repeats s
5. Deletions and amplifications of triplet repeats 9
6. I n h i b i t i on of DNA replication and initiation of h o m o l o g o us
recombination by SbcCD protein 9
7. Conclusions
Ml
A c k n o w l e d g e m e n ts 11
References
12
2 Double-strand break repair and V(D)J recombination ib
BELINDA K SINGLETON AND PENNY A. IEGCO
action it
2. V(D)J recombination
ib
2.1 Recognition and cleavage of the signal sequences 17
2.2 Processing and joining the dsbs 17
