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J Biol Chem, Vol. 274, Issue 37, 25975-25978, September 10, 1999
From the Lineberger Comprehensive Cancer Center and Department of
Pathology, University of North Carolina Medical School, Chapel
Hill, North Carolina 27599-7295
The occurrence of triplet-repeat expansion (TRE)
during transmission of genetic information is involved in many
neurological and neuromuscular diseases including Fragile X syndrome
and myotonic dystrophy. DNA slippage during replicative synthesis
appears to cause TRE. The causes of DNA slippage, however, remain
mostly unknown. We investigated the effects of abasic sites on the
occurrence of TRE during DNA replication in vitro using
Escherichia coli Klenow polymerase I as the model
polymerase. Here we show that a single abasic site analog, synthesized
in the triplet-repeat tract at the 5' end of the template strand,
induced dramatic TRE during DNA synthesis. The amount of TRE induced
decreased when the abasic site was moved to the middle of the repeat
tract, consistent with effectively decreasing the length of the repeat
tract. Placing the abasic site in the primer did not induce TRE. TRE
was sequence-dependent. The damage-induced increase in
growing strand TRE depended on the sequence of the growing strand
repeat as AAT ~ ATT > CAG > CTG. The expansions
required replication from a primer complementary to the repeat tract.
The expanded tracts were sequenced and contained multiple additions of
the original repeat. The results imply that DNA damage can play a
significant role in generating TRE in vivo.
The occurrence of triplet-repeat expansion
(TRE)1 during transmission of
genetic information is involved in many diseases including Fragile X
syndrome (1-3), the most common form of mental retardation; myotonic
dystrophy, a neuromuscular disorder; and several neurodegenerative disorders (1, 2). DNA slippage (4) during replicative synthesis is
believed to be a major contributor to TRE in vivo (5-8),
because elimination of recombination in yeast (9) and in
Escherichia coli (10) does not influence TRE, whereas
elimination of mismatch repair does (10, 11). Pausing or blockage of
DNA replication has been proposed to promote slippage by giving the DNA
replication complex more time to dissociate and form misaligned DNA
intermediates (12, 13). Hairpins (14-18), bulges (19, 20), tetraplexes
(18, 21), and possibly "slipped" structures (22, 23) have been
proposed to promote DNA slippage. The structures were proposed to act
either as intermediates, by their formation within the repeat or by
blocking or pausing replication toward the end of the repeat (12, 24)
or a combination of both (13, 17, 24). Replication pause sites are hot
spots for nucleotide misincorporation (25). If pausing also induces
slippage, the occurrence within the repeat tract of DNA damage that
blocks DNA replication could profoundly effect TRE.
Studies of replication of DNA template-primers in vitro with
DNA polymerase alone are important for their potential ability to
uncover mutation mechanisms. Replication of triplet-repeat tracts
in vitro shows TRE (26-29). Here, we report the effects of
tract length, tract sequence, and DNA damage on TRE during DNA
replication in vitro. The abasic site analog tetrahydrofuran (THF) was used as the model DNA damage lesion. Abasic sites and THF
block DNA replication (reviewed in Refs. 30 and 31), and the abasic
site is one of the most common lesions that arise in cellular DNA (32).
THF was synthesized in the triplet-repeat tracts separately in the
template and in the primer strands. Replication using E. coli Klenow pol I as the model polymerase and primed from within
the repeat tract demonstrated that THF in the template strand greatly
enhanced TRE during DNA synthesis.
Materials--
Oligodeoxyribonucleotides (oligonucleotides) were
synthesized by the Lineberger DNA synthesis facility using an Applied
Biosystems automated synthesizer. Oligonucleotides were synthesized as
templates for DNA replication. The templates contained ACTGTGTCTGTC
(Ua) at the 5' end and GCGACCTGATCC (Ub) at the
3' end, surrounding the triplet repeats (ATT)10,
(ATT)20, (AAT)10, (AAT)20,
(CTG)10, (CTG)20, (CAG)10, and
(CAG)20, as indicated in figure legends. Templates
containing 10-repeat tracts were also synthesized to contain the abasic
site analog THF (phosphoramidite purchased from Glen Research) in place
of the last base at the 5' end of the repeat tract. Primers were
synthesized to be complementary to either Ub or to the
repeat tract. The latter were three repeats in length. To study the
effect of THF placement, THF was also placed at the beginning of the
fourth repeat of (ATT)10 in place of A,
Ua(ATT)3(FTT)(ATT)6Ub,
where F is THF. THF was also synthesized in place of the middle residue
of the primer to give AATAFTAAT. All of the templates were synthesized
to contain a three-carbon spacer (Glen Research) at their 3' terminus
that can not be removed or extended by DNA polymerase (not shown).
Assays--
The replication reaction contained 50 mM
Tris-HCl (pH 7.8), either 0.3 mM or 0.5 mM
MgSO4, as indicated in the figure legends, 0.1 mM dithiothreitol, 0.1 mM of all four dNTPs, 5 µM of the primer and template, and either 0.1 unit/µl
or 0.2 unit/µl of Klenow pol I (Promega). For annealing, primer and
template were mixed, incubated at 90 °C in 50 mM
Tris-HCl and MgSO4, and allowed to cool to room
temperature. The reaction was started by addition of dithiothreitol,
dNTPs, and polymerase and was incubated at the indicated temperatures
for 2 h. The reactions were stopped by addition of EDTA to 23 mM and by cooling to 4 °C. Reaction products were
resolved by either 2% agarose native or alkaline gel electrophoresis.
The gels were either stained with ethidium bromide or, if radiolabeled
substrates were used, analyzed using a Storm PhosphorImager (Molecular
Dynamics). All of the templates and primers were tested individually
for their ability to support expansion under the above reaction
conditions. Only primed templates supported TRE under our reaction conditions.
DNA Sequencing--
To determine the sequences of the TREs, the
expanded primers were extended to the end of the template 5'-terminal
unique sequence (Ua). For reactions involving abasic sites,
the reaction products were melted and reannealed twice. First, the
reaction products were melted and the extended primers were reannealed
to templates identical to the reaction templates but lacking the abasic
site. The new annealed template-primers were extended with Klenow
polymerase to the end of the template downstream 5' unique sequence
(Ua). Second, the extended primer strand was melted and
reannealed to complementary sequencing primer for sequencing by
automated methods.
Restriction Enzyme Digestion--
Restriction enzymes
BbvI (New England Biolabs), which recognizes and cleaves the
sequence GCAGC(8/12), and AciI, BsgI,
MboII, MnlI, NlaIII, and
PstI (New England Biolabs), and ThaI (Life
Technologies, Inc.), which recognize variants of the CTG repeat, were
used according to the manufacturer's recommended conditions.
We analyzed the effect of THF on TRE during DNA replication
in vitro. Template-primers were constructed to contain a
repeat tract flanked by two different unique sequences (Ua
and Ub in Fig. 1). The 3'
ends of the templates were blocked by a three-carbon spacer (Glen
Research), which blocks extension by polymerase (not shown). Primers
were constructed to be complementary to either the triplet-repeat tract
(floating primer) or the unique flanking sequence 3' to the repeat
tract (fixed primer). The former mimics the sliding model (6, 7) for
expansion by DNA slippage and the latter mimics models involving bulge
and hairpin intermediates (14-18). Replication from a floating primer
generates long TREs under conditions of low Mg2+ (29). The
presence of unique sequences flanking the repeat tract, however,
significantly reduces the amount of TRE. Control experiments, using
end-labeled template and primer, demonstrated that templates and
primers by themselves did not support DNA synthesis by Klenow
polymerase (not shown). DNA synthesis and TRE were detectable only when
annealed primer-template was used for DNA replication.
The model abasic site analog THF (Fig. 1A) was introduced at
a single position at the 5' end of the 10-repeat tract just before the
unique flanking sequence (Fig. 1B). Replication with both floating and fixed primers is portrayed in Fig. 1B,
1 and 2, respectively. The presence of THF at the
end of the repeat tract gave significant TRE with the primer:template
(AAT)3:U(FTT)(ATT)9U (Fig.
2), whereas there was little expansion in
the absence of THF under these conditions. The conditions used
previously to observe significant amounts of spontaneous TRE during DNA
replication in vitro lacked unique sequences flanking the
template repeat (26-29). The amount of THF-induced expansion that
occurred at 42 °C increased with increased reaction time to
approximately 1500 bases for primer AAT after 4 h (Fig. 2).
Significant THF-induced expansion was also observed at 37 °C (Fig.
3, lane 3). Shifting the
position of THF to the middle of the repeat tract (see "Experimental
Procedures" for sequence) decreased the amount of expansion observed
at 37 and 42 °C. The result is consistent with effectively
shortening the length of the repeat tract in the template (Fig. 3,
lanes 4 and 9). Placing THF in the middle of the
primer did not enhance TRE (Fig. 3, lanes 5 and
10) and instead appeared to reduce the amount of fill-in replication product as measured by the intensity of the lowest molecular weight band (lanes 5 and 10).
COMMUNICATION
Abasic Sites Induce Triplet-repeat Expansion during DNA
Replication in Vitro*
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
View larger version (12K):
[in a new window]
Fig. 1.
The abasic site analog THF was synthesized at
a unique position within the repeat tract. A, The model
abasic site THF. B, 1, replication from a
"floating" primer complementary to the repeat tract; 2,
replication from a "fixed" primer complementary to the 3' unique
flanking sequence Ub. THF is shown at the 5' end of the
repeat tract. Filled circle, THF; arrows,
replication primers; boxes, unique flanking sequences
Ua and Ub; X, three carbon block on
template to prevent extension by polymerase.
View larger version (74K):
[in a new window]
Fig. 2.
THF-dependent increases in
expansion of the primer strand with increasing time. The template
was Ua(ATT)10Ub for unmodified and
Ua(FTT)(ATT)9Ub, where
Ua and Ub are defined in Fig. 1 legend and F is
THF. The floating primer was (AAT)3. Assay conditions were
as described under "Experimental Procedures" and the incubation
temperature was 42 °C for the times indicated. Lanes 1 and 6, base pair markers; lanes 2 and
7, template-primer without and with THF, respectively, in
the absence of polymerase; lanes 3-5, replication of
template-primer lacking THF. Products were resolved by 2% agarose gel
electrophoresis. lanes 8-10, replication of template-primer
containing THF.
View larger version (115K):
[in a new window]
Fig. 3.
Comparison of effect on TRE of THF in the
middle versus the 5' end of the template repeat and in
the primer strand. Lanes 1 and 6, base pair
markers; lanes 2 and 7, no THF; lanes
3 and 8, THF located at the 5' end of the repeat tract
(e); lanes 4 and 9, THF located in the middle of
the template repeat tract (m); lanes 5 and 10,
THF located in the middle of the primer (p). Assay
conditions are described under "Experimental Procedures," and
incubation was at 37 and 42 °C, as indicated, for 2 h.
Replications of all four of the 10-repeat templates with and without
THF were compared under identical reaction conditions. The order of
primer repeat expansion induced by THF, located at the 5' end of the
template repeat tract, was ATT 
AAT > CAG > CTG
(summarized in Fig. 4). A small fraction
of longer replication products in the absence of THF is visible in Fig.
4, lanes 2 and 4. These products appear to be the
product of processive replication, since only a small fraction of
substrate is extended to long product. Alternatively, the THF results
imply that a low level of oligonucleotide with contaminating damage
within the repeat could be responsible for the small background of long
products visible in Fig. 4.
|
Sequencing of the expanded ATT- and CAG-repeat primer DNA strands (see
"Experimental Procedures") showed that the expansion sequences
mimicked the primer repeat (not shown). CAG expansion products, from
reactions in which the primer and template strands were separately
labeled, were analyzed on alkaline gels. The results demonstrated that
only the primer strand (and only from floating primers) was expanded
(Fig. 5). The labeled products were also digested with restriction enzymes and analyzed on denaturing gels (Fig.
5, lanes 3 and 6). Both strands of the expansion
products were cleaved by BbvI (GCAGC8/12) but not by enzymes
that recognize variants of the CAG repeat (AciI,
BsgI, MboII, MnlI, NlaIII,
PstI, and ThaI) (not shown). The presence of
multiple bands in lane 4 (template only) is probably due to
residual secondary structure caused by hairpin formation by CTG repeats
(14-18). No breakage at the abasic site was detectable above
background. Strand breakage caused by the THF site would have given a
band in Fig. 5 corresponding to a labeled 12- or 13-mer (Fig. 5,
lane 4).
|
Using agarose gel electrophoresis, we analyzed the effects of
temperature and tract length on replication of CTG template repeat
tracts. Ten- and twenty-repeat tracts with and without THF were
replicated. Only floating primers (i.e. primers
complementary to the repeat tract) gave detectable levels of expansion.
Increasing temperature increased TRE both with and without THF. The
presence of THF in the template repeats enhanced expansion of triplet
repeats over that without THF at all temperatures studied (Fig.
6). 20-repeat tracts reproducibly gave
significantly more TRE than 10-repeat tracts. This was true at all
temperatures studied whether or not THF was present. The difference
between TRE with and without THF in 20-repeat tracts was not as
dramatic as that for 10-repeat tracts. This was because of the large
amount of "spontaneous" TRE for 20-repeat tracts. Similar increases
in TRE with increasing repeat-tract length were found for all of the
template-primers (not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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The effects of an abasic site in the triplet-repeat tract on the occurrence of TRE during DNA replication in vitro were determined. The model abasic site THF blocks DNA replication (33-36). Introduction of THF into a triplet-repeat tract was found to dramatically increase TRE during replicative synthesis in vitro. Low Mg2+ concentration was used to generate dramatic TRE (29) similar to the type II TREs observed in Fragile X syndrome and myotonic dystrophy (1-3). Although the Mg2+ concentration was less than that assumed to be at the replication fork in vivo, it served to destabilize the DNA so that DNA slippage is amplified enabling us to study factors that effect its occurrence in vitro. The expansions were only detected when a primer was used complementary to the repeat-tract sequence, rather than complementary to the unique upstream flanking sequence. Expansion by priming within the repeat tract was seen also in the absence of THF but to a much lesser extent. A sliding primer could occur in vivo by location of an Okazaki primer entirely within the repeat tract (6, 7). Alternatively, DNA damage or repair could produce a nick in the growing strand within the repeat tract, while the growing-strand end is located within the repeat tract. This would be more likely if replication were stalled within the repeat tract because of a blocking DNA lesion. Moreover, abasic sites may stimulate slippage by keeping the replication complex within the "slippery surface" of the triplet repeat. Characterization of the expansion products showed that only the primer strand was expanded. DNA sequencing showed that the AAT and CAG expansions were the same sequence as the starting repeat tracts. Restriction enzyme digestion of the CAG TRE products with and without THF showed that the template strands as well as the primer strands were digested. Digestion of the template strand means that it was not displaced from the primer strand as would occur if expansion were caused by a strand-switching mechanism. In addition, digestion of the primer strand confirmed that the triplet-repeat sequence was uniform over the entire expanded tract as shown by direct sequencing. Moving the abasic lesion from the end to the middle of the repeat tract reduced the amount of TRE. Moving the lesion, which blocks replication, closer to the beginning of the repeat effectively reduces the size of the repeat tract available to polymerase. We showed that under our conditions, longer triplet repeats are more susceptible to TRE than shorter triplet repeats. This is consistent with results in vivo (1, 2, 7) and with our understanding of DNA slippage (4, 20). Placing the lesion in the primer instead of the template gave no detectable TRE and decreased the intensity of the filled-in template-primer band. The result implies that THF in the primer interfered with replication priming probably by destabilizing the template-primer duplex.
It has been suggested that DNA slippage should be enhanced by an idling
polymerase at a pause site caused by a DNA structure or bound protein
(12). The suggestion, if correct, leads to the hypothesis that DNA
damage that blocks replication could have profound effects on TRE. To
test the hypothesis in vitro, we introduced the abasic site
analog THF into triplet-repeat tracts and demonstrated that its
presence dramatically increased the occurrence of expansion. This
demonstration only has importance in vivo if abasic sites occur within repeat tracts with a high enough frequency to have meaningful impact. Abasic sites arise spontaneously through hydrolysis of DNA N-glycosyl bonds (37) and are estimated to occur at a rate of 10,000 abasic sites/cell/day under physiological conditions (37). The steady-state levels of abasic sites vary with the tissue
sampled from a low of ~1 abasic site per 106 nucleotides
to a high of 35 abasic sites per 106 nucleotides (38).
Chemical exposures of cells in culture induced higher levels (38).
Thus, given triplet-repeat tracts of 102 nucleotides and
spontaneous steady-state levels of abasic sites, we would expect
0.0001-0.0035 abasic sites per given repeat tract. Assumption that the
presence of an abasic site in the triplet-repeat tract results in a
104-fold (it could be significantly higher) increase in TRE
per replicative event gives up to a 35-fold increase in TRE rates at
that repeat tract. This calculation assumes that the repeat tract is a
target for DNA damage equivalent to the bulk DNA. The latter assumption may underestimate levels of damage to triplet repeat tracts. Some repeats show mobilities during gel electrophoresis different from unique sequence DNA of the same size, indicative of unique structures (39). It is possible that repetitive DNA is a better target for DNA
damage than unique sequence DNA. In addition, DNA lesions induced by
endogenous and exogenous sources increase abasic sites by spontaneous
depurination and by removal of damaged bases by DNA glycosylases
(reviewed in Ref. 30). The experiments described here offer the first
indications, to our knowledge, that DNA damage can induce large
expansions of triplet repeats. The results imply that DNA damage plays
a role in TRE diseases such as myotonic dystrophy and Fragile X syndrome.
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FOOTNOTES |
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* This work was supported in part by National Institutes of Health Training Grant 5-T-32-ES07017.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Lineberger
Comprehensive Cancer Center, Chapel Hill, NC 27599-7295. Tel.:
919-966-8208; Fax: 919-966-3015; E-mail: mdtopal@med.unc.edu.
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ABBREVIATIONS |
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The abbreviations used are: TRE, triplet-repeat expansion; THF, tetrahydrofuran; pol I, polymerase I.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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 J. L. Callahan, K. J. Andrews, V. A. Zakian, and C. H. Freudenreich Mutations in Yeast Replication Proteins That Increase CAG/CTG Expansions Also Increase Repeat Fragility Mol. Cell. Biol., November 1, 2003; 23(21): 7849 - 7860. [Abstract] [Full Text] [PDF]
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B. L. Heidenfelder, A. M. Makhov, and M. D. Topal Hairpin Formation in Friedreich's Ataxia Triplet Repeat Expansion J. Biol. Chem., January 17, 2003; 278(4): 2425 - 2431. [Abstract] [Full Text] [PDF]
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K. Nozawa, M. Suzuki, M. Takemura, and S. Yoshida In vitro expansion of mammalian telomere repeats by DNA polymerase {alpha}-primase Nucleic Acids Res., August 15, 2000; 28(16): 3117 - 3124. [Abstract] [Full Text] [PDF]
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 P. Jin and S. T. Warren Understanding the molecular basis of fragile X syndrome Hum. Mol. Genet., April 1, 2000; 9(6): 901 - 908. [Abstract] [Full Text] [PDF]
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J. P. Jakupciak and R. D. Wells Gene Conversion (Recombination) Mediates Expansions of CTG{middle dot}CAG Repeats J. Biol. Chem., December 15, 2000; 275(51): 40003 - 40013. [Abstract] [Full Text] [PDF]
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