DNA Repair 37 (2016) A35–A39

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DNA Repair
journal homepage: www.elsevier.com/locate/dnarepair

Historical Perspective

A history of the DNA repair and mutagenesis field

The discovery of base excision repair
Errol C. Friedberg
Department of Pathology, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX 75390, United States

a b s t r a c t

This article reviews the early history of the discovery of an DNA repair pathway designated as base excision repair (BER), since in contrast to the
enzyme-catalyzed removal of damaged bases from DNA as nucleotides [called nucleotide excision repair (NER)], BER involves the removal of damaged or
inappropriate bases, such as the presence of uracil instead of thymine, from DNA as free bases.
© 2015 Published by Elsevier B.V.

1. Introduction

A previous article in this series on the history of the discovery of

DNA repair mechanisms addressed the identification of enzymatic
photoreactivation, the first discovered DNA repair process. From a
chronological point of view addressing the history of the discovery
of nucleotide excision repair (NER), the first mode of excision repair
of DNA to be revealed, is a logical sequel. Readers interested in this
historical account are referred to a paper published several years
ago [1].
The present essay traces the early history of the discovery of
an enzymatic DNA repair mode by which damaged or inappropri-
ate bases (a prime example being the presence of uracil instead
of thymine) are removed from DNA as free bases rather than as
nucleotides, as is the case during NER. My Stanford colleagues James
Duncan and Lenore Hamilton and I suggested that this mode of
excision repair be designated as base excision repair (BER) to dis-
tinguish it from nucleotide excision repair (NER) [2].
2. The discovery of DNA glycosylases
The discovery of BER is credited to Tomas Lindahl (Fig. 1), who
received the 2015 Nobel Prize in Chemistry for his contributions to
the mechanism of this DNA repair mode. I first met Tomas in the
summer of 1971 while attending a meeting on DNA repair at Johns
Hopkins University. Having recently initiated my own research pro-
gram on DNA repair at Stanford University I was keen to meet
Tomas, and introduced myself to him at the end of his talk – an
overture that marked the beginning of a long-standing scientific
and personal relationship that endures to the time of this writing.
In late 1979 and early 1980 I spent a sabbatical in Tomas’s labo-
ratory at the University of Göteborg (Gothenburg), Sweden. Over
the many years since 1971 our relationship has been characterized
by discussions about numerous and varied aspects of DNA repair
Fig. 1.
– as well as a shared passion for gastronomic delights, notably
good wine. Tomas acquired his taste for fine wines while a medical
student, and during his tenure as a professor at the University of
Göteborg he was an official wine taster for a Swedish magazine on
food and wine, a luxury that afforded him the exquisite pleasure of
tasting many fine wines (and presumably some not so fine).
Lindahl received his early scientific training as a medical student
at the Karolinska Institute, located in Solna, a town in the Stock-
holm urban area. More interested in biomedical research than in
the practice of clinical medicine, Lindahl associated himself with
Einar Hammarsten, a Swedish physician who had recently retired
from his position as professor of chemistry and pharmacy at the
Karolinska. A member of the Royal Swedish Academy of Sciences,
Hammarsten was for many years a member of the Nobel Committee
for Physiology or Medicine. Described by Lindahl as a small, wiry
man with intense grey-green eyes, Lindahl recalled that he was
once taken into a cold room by Hammarsten, who wanted to check
on a chromatography column that he was running. While in that
frigid environment Hammarsten began a lengthy discourse with
Lindahl – a conversation that might easily have been conducted in
the comparative warmth outside the cold room!

http://dx.doi.org/10.1016/j.dnarep.2015.12.003
1568-7864/© 2015 Published by Elsevier B.V.
A36 E.C. Friedberg / DNA Repair 37 (2016) A35–A39
Following graduation from medical school in the mid-1960s
Lindahl made a commitment to a research career and elected to
join Jacques Fresco’s laboratory at Princeton University as a post-
doctoral fellow. Fresco had a special interest in the structure and
conformation of tRNA, a research area that Lindahl soon immersed
himself in. While so engaged his experiments were frequently
plagued by spontaneous decomposition of the tRNA, especially
when he carried out procedures at high temperature. Surprised by
the innate chemical instability of this nucleic acid and reasonably
assuming that DNA, a much larger nucleic acid, was also subject to
measurable levels of spontaneous chemical change Lindahl decided
then that upon his return to Sweden he would investigate sponta-
neous damage in DNA and search for enzymes that might facilitate
its repair.
On his return to the Karolinska Institute as an assistant pro-
fessor Lindahl examined the rates of hydrolysis of chemical bonds
in radioactive DNA as a function of temperature and pH, and
established that spontaneous hydrolysis of DNA transpires at a
biologically significant rate under physiological conditions. In an
article published in Nature in 1993 he reviewed the literature on
the instability and decay of the primary structure of DNA [3]. Not-
ing that the 2 -OH group of ribose confers significant vulnerability
to spontaneous decomposition in RNA, Lindahl pointed out that
the “chemical price paid for the greatly increased resistance of the
nucleic acid phosphodiester bond gained by the absence of the
sugar 2 -OH group in DNA is a labile N-glycosyl bond.” He predicted
that an Escherichia coli cell growing with a generation time of 40 min
at 37 ◦ C would lose one purine every two generations. He estimated
that a mammalian cell containing about 800 times more DNA than
E. coli, which grows with a generation time of 20 h, about 12,000
purines are lost as free bases from DNA per cell generation. Assum-
ing that all these apurinic sites in DNA are repaired, the extent of
base excision repair in our cells is clearly prodigious. Lindahl noted
too that in addition to the problem of the intrinsic lability of glycosyl
bonds, DNA base residues are susceptible to hydrolytic deamina-
tion, cytosine and its homolog 5-methylcytosine being the main
targets for this reaction. The deamination rates of these bases were
defined experimentally by following their conversion to uracil or
thymine, respectively.
Having defined a plethora of spontaneous insults to DNA Lin-
dahl reasoned that it was likely that during the course of evolution
living cells acquired mechanisms for the repair of some if not
all of these lesions. He initially set his sights on a search for an
enzyme that might remove uracil residues arising from the spon-
taneous or environmentally induced deamination of cytosine, and
in 1974 he announced the identification and partial purification of
an enzyme that he initially called uracil-N-glycosidase, but subse-
quently changed the name to uracil-N-glycosylase [4]. “The enzyme
clearly acted in a hydrolytic way, hence the term ‘glycosidase”’ Lin-
dahl explained. “Additionally, the standard textbooks referred to
the sugar-base bond as an N-glycosidic bond. But I received agitated
letters from self-appointed nomenclatural experts who stated that
the term ‘N-glycosidic bond’ did not exist and that the correct term
was ‘glycosyl bond.’ I didn’t pay much attention to these critics at
first, but with increasing hassle about this issue I finally reluctantly
agreed to change the term ‘glycosidase’ to ‘glycosylase”’ [5].
Prior to Lindahl’s discovery of an enzyme that liberated free
uracil from a polynucleotide substrate all previously described
enzymes that attacked DNA generated acid-soluble nucleotide
or oligonucleotide products. Hence, they could be conveniently
assayed by their presence in the soluble fraction of acid-
precipitated DNA. A significant trap for misinterpretation of such
assays is that free bases are also acid-soluble and hence an enzyme
activity such as the uracil-N glycosylase discovered by Lindahl
might be easily missed. But since he was specifically focused on
a search for an enzyme activity that released free uracil for DNA, he
Fig. 2.
astutely examined the products of his enzyme reactions by chro-
matography rather than simply measuring acid-soluble products.
Despite these cautions he enjoyed a stroke of luck without which
he too might have run into interpretive complexities. In later con-
versations he recounted to me that: “I was lucky in having chosen,
more or less accidentally, a chromatographic system that clearly
separated uracil and deoxyuridine in product analysis. They often
co-chromatograph and this could have been misleading” [5].
Lindahl also related that he did “dare believe in the existence of
such a novel enzyme until I succeeded in doing the technically more
difficult experiment of showing that treatment of a polynucleotide
substrate containing scattered U residues with a partially purified
enzyme caused the introduction of alkali-labile sites but no chain
breaks” [5].
In the interests of historical completeness I relate my own
encounter with what was almost certainly uracil DNA glycosylase
at about the same time. The article on the history of our understand-
ing of NER referred to in the introduction recounts the discovery of
this repair process in E. coli by the late Richard (Dick) Setlow and
his colleague William (Bill) Carrier. Sometime in early 1974 Ann
Ganesan, a colleague in the Stanford Department of Biology visited
the Setlow’s laboratory. Upon her return Ann informed me that
Setlow had told her that an enzyme discovered by the late Larry
Grossman (Fig. 2) in extracts of the bacterium Micrococcus luteus,
which was known to specifically attack pyrimidine dimers in DNA,
also attacked DNA containing uracil. Work that was initiated while
I was (despondently) serving in the US Army at the Walter Reed
Army Institute for Research from 1968 to 1970 (a consequence of
having being drafted into the US Army during the Vietnam con-
flict), had characterized an enzyme encoded by bacteriophage T4
that in due course was shown to have properties identical to that of
the enzyme from M. luteus [6,7]. Notably, the enzyme also specif-
ically and uniquely recognized pyrimidine dimers in DNA as a
substrate [8,9]. This substrate specificity rendered the phage T4
enzyme a convenient and sensitive reagent for detecting pyrimi-
dine dimers in DNA and was widely used for this purpose. I was
thus convinced that the enzyme activity that Setlow had stum-
bled on was a contaminant in the M. luteus enzyme preparations
he had tested. Nonetheless my colleagues and I duly examined our
purified preparations of the phage T4 pyrimidine dimer-specific
enzyme and reassured ourselves that it did not attack DNA isolated
from a Bacillus subtilis phage called PBS2, which naturally contains
uracil instead of thymine in its genome. We therefore concluded
that the enzyme preparations that Setlow had examined were con-
taminated by an activity that degrades uracil-containing DNA.
As positive controls for these experiments extracts of uninfected
E. coli and B. subtilis were observed to readily attack uracil-
containing PBS2 DNA. Based on these results I was interested in
addressing two obvious issues. Given the presence of an enzyme
in B. subtilis that attacks uracil-containing DNA I was curious as to
how the genome of phage PBS2 escapes degradation after the phage
infects B. subtilis. I was naturally also interested in learning more
about the newly discovered enzyme activity that attacks uracil-
 E.C. Friedberg / DNA Repair 37 (2016) A35–A39
containing DNA, which I tacitly assumed was a nuclease. Members
of my laboratory were then fully engaged in other experiments.
However, I was ultimately able to persuade one of them to put
aside his experiments for a while and address the first question.
It was soon revealed that very soon after infecting B. subtilis
phage PBS2 expresses an inhibitor of the enzyme that attacks uracil-
containing DNA. In later years my colleagues and I characterized
this inhibitor [10], which subsequently became a useful reagent for
specifically inhibiting uracil-DNA glycosylase in vitro. While in the
early stages of experiments to address the second issue of interest –
purifying and characterizing the putative nuclease in B. subtilis that
attacks uracil-containing DNA, I encountered Lindahl’s paper in the
September 1974 issue of the PNAS, announcing the discovery of a
enzyme in E. coli that catalyzes the release of free uracil from DNA.
I soon established that the properties of the B. subtilis enzyme were
essentially identical to those of the uracil-DNA glycosylase discov-
ered by Lindahl [11]. Since PBS2 DNA contains U-A base pairs our
experiments providentially revealed that the substrate specificity
of the E. coli enzyme discovered by Lindahl was not dependent on
the presence of U-G mispairs. Lindahl later demonstrated that the
enzyme even removes uracil from single-stranded DNA.
History will of course never reveal whether or not absent Lin-
dahl’s publication in September 1974 my colleagues and I would
have independently discovered uracil-DNA glycosylase, though I
would like to think that such an outcome would have emerged in
due course! But the critical reality is that focused as he was on a
search for an enzyme activity that removes uracil from DNA, Lin-
dahl astutely established an assay that included the possibility that
uracil might be released from DNA as the free base rather than as a
nucleotide or part of oligonucleotide fragments, as had been shown
by Setlow to be the case with thymine dimers during NER. My
own focus was on the extensive degradation of phage PBS2 uracil-
containing DNA when it infected B. subtilis, the products of which
would be readily observed by measuring radioactivity in the acid-
soluble fraction of reaction mixtures that included DNA containing
radiolabeled uracil. I had no immediate cause to consider the pos-
sibility that uracil might be present in the acid-soluble fraction as
the free base.
In a book entitled Correcting the Blueprint of Life – An Historical
Account of the Discovery of DNA Repair Mechanisms, published in
1997 I recounted fragments of a discussion between Francis Crick
and the science historian Horace Judson, author of The Eighth Day
of Creation – Makers of the Revolution in Biology, on the nature of
discoveries. Judson offered the comment to Crick that “discovery,
examined closely – seemed curiously difficult to pin to a moment
or to an insight, or even a single person.” To which Crick responded:
“I think that’s the nature of discoveries, many times: that the
reason they’re difficult to make is that you’ve got to take a series
of steps, three or four steps, which if you don’t make them you
won’t get there, and if you go wrong in any one of them you
won’t get there. It isn’t a matter of one jump – that would be
easy. You’ve got to make several successive jumps. And usually
the pennies drop one after another until it all clicks. Otherwise
it would be too easy! [12].
Other investigators encountered what was likely uracil-DNA
glycosylase activity while pursuing unrelated questions. As early
as 1958 Arthur Kornberg and his colleagues had shown that the
DNA polymerase he discovered could utilize dUTP as a precursor for
DNA synthesis in vitro. When Huber Warner and Merle Wovcha at
the University of Minnesota synthesized DNA with “purified” E. coli
DNA polymerase in the presence of dUTP they observed nicking
of the DNA at sites of uracil incorporation and erroneously con-
cluded that the 5 → 3 exonuclease activity of DNA polymerase
I possessed an intrinsic uracil-specific endonuclease. They pub-
lished these results in a paper entitled: Synthesis and Nucleolytic
A37
Degradation of Uracil-containing Deoxyribonucleic acid by E. coli
Deoxyribonucleic Acid Polymerase I [13]. These studies provide a
perfect example of the well-worn aphorism attributed to Arthur
Kornberg: “don’t waste clean thoughts on dirty enzymes.”
The discovery of uracil-DNA glycosylase opened the door to the
discovery of multiple other DNA glycosylases. By the mid-1990s
close to a dozen such enzymes were known to exist. Surprisingly,
the catalogue of known DNA glycosylases includes the bacterio-
phage T4 pyrimidine dimer-specific enzyme mentioned above, as
well as a very similar enzyme in the bacterium M. luteus, discov-
ered earlier by the late Larry Grossman. I was originally confident
that my colleagues and I had discovered a new nucleotide excision
repair pathway and that the phage T4-encoded enzyme would be
shown to catalyze the endonucleolytic incision of DNA close to sites
of pyrimidine dimers, thereby setting the stage for subsequent exci-
sion of pyrimidine dimers. However, to my surprise the enzyme was
shown to catalyze cleavage of the glycosyl bond of the 5 thymine in
thymine dimers in DNA, generating an apyrimidinic site in the DNA,
while the two thymine residues remained dimerized [14]. Identical
results were obtained by Grossman and his colleagues with respect
to the enzyme from M. luteus.
3. The discovery of apurinic-apyrimidinic endonucleases
and lyases
The catalytic action of a DNA glycosylase leaves sites of
base loss in DNA. Hence, this class of enzymes essentially
trades one type of DNA damage for another. The completion
of BER initiated by a DNA glycosylase requires incision of the
sugar-phosphate backbone at the apurinic/apyrimidinic (AP) site.
Two classes of enzymes are known to achieve this hydroly-
sis, designated as apurinic/apyrimidinic (AP) endonucleases and
apurinic/apyrimidinic (AP) lyases.
The first AP endonuclease, designated endonuclease II of E. coli
was unwittingly discovered when I was a post-doctoral fellow in
the late David Goldthwait’s laboratory at Western Reserve Uni-
versity from 1966 to 1968 [15,16]. I use the word “unwittingly”
advisedly since when I joined Goldthwait’s laboratory the research
project that he assigned to me was to go in search of anticipated
endonucleases involved in genetic recombination.
As detailed in an autobiographical article published in this
journal a few years ago [17] Goldthwait (Fig. 3) believed that
endonucleases involved in genetic recombination would cut DNA
in a highly specific manner and was interested in establishing the
molecular basis of this specificity. In a paper published in the Cold
Spring Harbor Laboratory Symposia in Quantitative Biology in 1968,
he and I wrote:
A model – that has not been formally excluded requires that
homologous pairing of two DNA molecules is a primary event
in recombination. This could conceivably occur through spe-
cific protein protein–DNA interactions that produce localized
disruption of normal base pairing in the 2 molecules. Such inter-
molecular association would result in an area of distortion of the
Fig. 3.
A38 E.C. Friedberg / DNA Repair 37 (2016) A35–A39
normal secondary structure of the DNA molecules at the region
of their pairing. An enzyme capable of recognizing this distor-
tion and restricted so that it could cleave only a single-strand of
DNA oriented in one direction (either 3 → 5 or vice versa) could
make the appropriate single-strand nicks to facilitate some sort
of intermolecular exchange – [18].
Goldthwait suggested that I attempt to generate localized con-
formational distortions of the DNA structure in vitro by treatment
of the DNA with the alkylating DNA methylmethane sulfonate. I
was then too biochemically naive to debate with my mentor that
alkylation might not generate any sort of distortion of the DNA
structure! Duly following Goldthwait’s advice I generated alkylated
and differentially radiolabeled DNA molecules so that recombina-
tion intermediates could be detected by sedimentation in sucrose
gradients, and searched for an enzyme activity that preferen-
tially attacked this substrate. I never recovered recombinational
intermediates! However, I discovered a novel endonuclease that
preferentially attacked alkylated DNA, which we dubbed endonu-
clease II (since it was the second E. coli endonuclease shown to
attack DNA). In subsequent studies Goldthwait and post-doctoral
fellow Sheikh Mumtaz Hadi demonstrated that the preferred sub-
strate for endonuclease II was in fact depurinated sites in DNA
presumably generated by enzymatic removal of alkylated bases
[19]. Hence, endonuclease II of E. coli is historically credited with
being the first AP endonuclease to be discovered.
In 1976 Bernard Weiss, then at the Johns Hopkins University,
demonstrated that the properties of a highly purified preparation
of a well-characterized enzyme in E. coli called exonuclease III were
identical to those of endonuclease II. Hence, endonucleases II and
exonuclease III of E. coli are almost certainly one and the same
enzyme. Weiss postulated that a single catalytic site in the enzyme
is able to recognize interstrand spaces in DNA generated either
by depurination or by spontaneous terminal unwinding of double
stranded DNA [20].
4. Apurinic/apyrimidinic lyases
Most DNA glycosylases are devoid of other catalytic activities.
As mentioned above, following release of the damaged or inappro-
priate base (such as uracil) incision of the DNA sugar-phosphate
backbone is effected by a physically distinct AP endonuclease.
However, the incubation of some DNA glycosylases (the phage T4
and M. luteus pyrimidine dimer DNA glycosylases being primary
examples) with substrate DNA is associated with the breakage of
phosphodiester bonds in vitro. In these instances DNA incision has
been shown to occur by a ␤ elimination reaction 3 to the AP site
and enzymes that catalyze such reactions are termed DNA lyases.
The first published indication of AP lyase activity (in 1985) was
by Germaine Grondal-Zocchi and Walter Verly [21], who suggested
that an AP endonuclease from E. coli designated as endonuclease IV
attacks AP sites in DNA by a ␤ elimination mechanism, the chemi-
cal details of which are not described here. A few years later Yoke
Kow and Susan Wallace [22] and Veronique Bailly and Walter Verly
[23] independently demonstrated that another AP endonuclease
in E. coli called endonuclease III (which is a DNA glycosylase that
removes ring-saturated or fragmented pyrimidines from DNA) is
also possessed with the ability to promote cutting of the sugar-
phosphate backbone by a ␤ elimination mechanism. In late 1989
Bailly and Verly formally suggested that “AP endonucleases” that
promote scission of the sugar-phosphate backbone of DNA by a ␤
elimination mechanism be designated as DNA lyases [24]. About
that time a DNA lyase activity of the phage T4 pyrimidine dimer
DNA glycosylase was reported in papers from the collaborative
laboratories of John Gerit, Lois Rabow, JoAnne Stubb and Philip
Bolton [25,26]. The sequential activity of the phage T4 (or M. luteus)
pyrimidine dimer-DNA glycosylases and their associated AP lyase
activities generate incisions of the DNA that allows for subsequent
excision of oligonucleotides that include the pyrimidine dimers.
5. Excision of the 5 deoxyribose residue
Following endonucleolytic incision of DNA by an AP endonucle-
ase the lingering 5 deoxyribose-phosphate residue must be excised
to generate a single nucleotide gap. A survey of known excision
activities in E. coli surfaced a 3 → 5 exonuclease active on sin-
gle stranded DNA by Richard Kolodner and Susan Lovett that is
encoded by the recJ gene, that can legitimately be referred to as a
deoxyribophosphodiesterase [27].
6. Reconstitution of BER in vitro
In 1994 Lindahl and Grigory Dianov reported the reconstitution
of BER of uracil in DNA in vitro using uracil-DNA glycosylase, the
AP lyase activity of endonuclease II, the Rec J exonuclease men-
tioned above, DNA polymerase I (to fill in the single nucleotide
gap), and DNA ligase to restore covalent integrity of the repaired
DNA [28]. Dianov and Lindahl also established a second pathway for
BER in vitro which is initiated in the same manner as that described
above, except that following AP endonucleolytic nicking adjacent
to the AP site subsequent strand displacement and DNA resynthesis
transpires as in NER and generates a longer repair patch.
BER is now firmly established as a fundamental DNA repair pro-
cess essential to the viability of all living cells and conceivably
evolved earlier than NER. One would also anticipate that BER is
a prominent DNA repair mode in thermophiles, in which the fre-
quency of spontaneous DNA damage is presumably significantly
higher than in organisms that grow at considerably reduced tem-
peratures. This author finds it remarkable that the literature on DNA
repair in thermophilic organisms is sparse.
7. Base insertion repair?
By way of concluding comments, one might anticipate that the
reverse reaction of that catalyzed by DNA glycosylases, i.e., the
direct insertion of a correct base into an AP site might exist in nature.
In 1979 Zvi Livneh, Dov Elad and Joseph Sperling reported the iden-
tification of an activity in extracts of E. coli that they claimed directly
inserts adenine or guanine into the appropriate apurinic sites in
double-stranded DNA from the corresponding deoxyribonucleo-
side triphosphates as the purine donor. [29] They designated this
putative DNA repair mode as “base insertion repair.”
When I spent a sabbatical period in Tomas Lindahl’s laboratory
in 1979–80 it was with the specific intention of reproducing the
results reported by Livneh et al. – to no avail. Additionally, in 1982
Kataoka and Sukiguchi published a paper in which they demon-
strated that the incorporation of purines into depurinated DNA can
be ascribed to the combined action of an AP endonuclease and DNA
polymerase I. Their abstract states: “An enzyme activity to incor-
porate labeled dATP or dGTP preferentially into depurinated DNA,
found in an extract of E. coli, does not seem to represent ‘purine
insertase’, but may be ascribed to a combined action of DNA poly-
merase I and AP endonuclease(s) on the basis of the following
findings. (1) The activity was found in polA+ but not in polA− cells.
(2) The base moiety and the ␣-phosphate group of the nucleotide
were equally incorporated into the DNA” [30]. In 1984 Bernard Mar-
tin and Nicole Sicard at the Centre de Recherche et de Geneticique
Cellullulaires in Toulouse, France also published a paper in which
they reported the failure to observe direct insertion of purines into
AP sites [31].
 E.C. Friedberg / DNA Repair 37 (2016) A35–A39
Acknowledgments
I thank Sam Wilson and Susan Wallace for valuable feedback
and advice.
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