From the Departments of Biochemistry and
¶ Medicine (Hematology/Oncology), Vanderbilt University School of
Medicine, Nashville, Tennessee 37232-0146
Received for publication, January 10, 2001, and in revised form, March 1, 2001
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ABSTRACT |
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Despite the importance of the topoisomerase II
DNA cleavage/rejoining cycle to genomic integrity, the mechanistic
details of religation are poorly understood. Topoisomerase II
utilizes covalent protein-DNA interactions to align the 5'-termini of
cleaved DNA for religation. However, because the enzyme does not form covalent bonds with the 3'-DNA termini, the basis for the alignment of
the 3'-ends is less clear. Three major possibilities exist. The
3'-termini may be positioned for religation (i) by base pairing to
their complementary DNA strands, (ii) by base stacking to the adjacent
residues, or (iii) by noncovalent interactions with topoisomerase II.
To distinguish between these possibilities, the ability of human
topoisomerase II The ability to ligate DNA chains is essential to all forms of life
(1-3). This activity is indispensable for nearly every process that
the genetic material undergoes in the cell, including replication,
recombination, and repair.
Although not ligases in the "classic" sense, topoisomerases
routinely join DNA chains as part of their fundamental cellular activities (4-6). To interconvert different topological states of DNA,
type II topoisomerases pass a double helix through a transient double-stranded break that is generated in a separate nucleic acid
segment (7-9). If these enzymes do not successfully rejoin the
double-stranded break, a number of deleterious events can occur
including chromosomal insertions, deletions, and translocations (8,
10). In extreme cases, the build up of topoisomerase II-mediated DNA
breaks triggers cell death pathways (11).
Because of the sensitivity of cells to the accumulation of these DNA
breaks, the religation activity of topoisomerase II has been exploited
as a target for cancer chemotherapy (8, 12-15). Drugs such as
etoposide, which is front-line therapy for a variety of human
malignancies (15, 16), increase topoisomerase II-generated DNA breaks
specifically by inhibiting the ability of the enzyme to rejoin cleaved
DNA molecules (8, 14, 17).
Despite the importance of the DNA religation reaction of topoisomerase
II to the critical cellular functions and chemotherapeutic potential of
the enzyme, the mechanistic details of this process are not completely
understood. In contrast to ligases, topoisomerase II carries out its
religation reaction within a covalent enzyme-DNA complex, known as the
cleavage complex (see Fig. 1; Refs. 7-9). This complex is formed
during the cleavage event so that the enzyme can maintain the integrity
of the genetic material throughout the strand passage process. The
bonds that link topoisomerase II to the DNA are established between
active site tyrosyl residues on each subunit of the homodimeric enzyme
and the 5'-terminal phosphates of the newly cleaved DNA strands
(18-20). Because the points of topoisomerase II-mediated scission on
the two strands are staggered by four base pairs, each cleaved chain
within the cleavage complex contains a four base single-stranded
cohesive end at its 5'-terminus (see Fig. 1).
In most cases, ligases rely heavily on base pairing to correctly
position the DNA termini for ligation (21, 22). However, the covalent
attachment of topoisomerase II to the 5'-termini of its ligation
substrate obviates the need for base pairing. In fact, human
topoisomerase II The role of base pairing in the positioning of the 3'-DNA termini for
religation is less clear. In contrast to the 5'-ends, the 3'-terminal
residues remain base paired to their complementary strand following
cleavage (see Fig. 1 and Ref. 18). Moreover, type II topoisomerases do
not form covalent attachments with the 3'-DNA ends (18). As a result,
it is not obvious whether the 3'-termini are positioned for religation
through base pairing. Alternatively, they may be aligned by base
stacking interactions with adjacent residues or through specific
noncovalent contacts with the enzyme.
If the DNA cleavage/religation cycle of eukaryotic type II
topoisomerases is to be fully understood, it is critical to determine how the enzyme positions the DNA termini for resealing. This issue takes on further importance because it is believed that many anticancer drugs that act by inhibiting topoisomerase II-mediated DNA religation do so by displacing the 3'-DNA termini within the cleavage complex (24-26). Therefore, to address the mechanism by which the enzyme positions the 3'-DNA termini, the ability of human topoisomerase II Preparation of Oligonucleotides--
A 40-base
oligonucleotide corresponding to residues 87-126 of pBR322 (18, 27)
and its complementary oligonucleotide were prepared on an Applied
Biosystems DNA synthesizer. The sequences of the top and bottom strands
were 5'-TGAAATCTAACAATG Topoisomerase II-mediated DNA Cleavage--
Human topoisomerase
II Topoisomerase II-mediated DNA Religation--
DNA religation
assays were carried out using a modification of the procedure of Kingma
and Osheroff (23). Cleavage/religation equilibria were established as
described above in cleavage buffer containing 5 mM
CaCl2. Kinetically competent topoisomerase II-DNA cleavage
complexes were trapped by the addition of EDTA (final concentration, 6 mM). NaCl was added (final concentration, 500 mM) to prevent recleavage. Religation was initiated by the
addition of MgCl2 (final concentration, 0.2 mM)
and terminated by the addition of 2 µl of 10% SDS at times up to
60 s. Alternatively, DNA cleavage/religation equilibria were
established as described in the previous section in cleavage buffer
containing 5 mM MgCl2, and religation was
initiated by transferring samples to 0 °C. Reactions were terminated
as above. Samples were prepared for electrophoresis and analyzed as
described above. The rate of DNA re-ligation was determined by
quantifying the loss of cleaved DNA.
Given the importance of topoisomerase II-generated DNA breaks to
the physiological and pharmacological functions of the enzyme, it is
critical to understand the mechanism by which topoisomerase II reseals
these breaks. During its scission event, the enzyme forms covalent
bonds with the newly generated 5'-DNA termini (18-20). Topoisomerase
II utilizes these covalent interactions to align the 5'-termini of the
breaks for religation (Fig. 1) (23).
to religate a series of oligonucleotides with
altered base pairing or base stacking at their 3'-termini was
determined. Substrates containing modifications that disrupted terminal
base pairing or base stacking with-out affecting the 3'-terminal base
were resealed at wild-type rates. In contrast, substrates that lacked
the terminal base (or contained an altered base) displayed very low
rates of religation. On the basis of these results, we propose
that topoisomerase II positions the 3'-DNA termini for religation
through noncovalent protein-DNA contacts.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
is able to efficiently religate substrates that
contain four consecutive abasic sites within the terminal cohesive ends
(thus eliminating all base pairing) (23). On this basis, it was
proposed that the type II enzyme correctly positions the 5'-DNA termini
for religation through covalent protein-DNA interactions (23).
to religate a series of substrates with altered base pairing or base
stacking at their 3'-termini was determined. Results indicate that
enzyme-mediated DNA religation requires the presence of a 3'-terminal
base, but does not require either terminal base pairing or base
stacking. These findings suggest that topoisomerase II positions the
3'-DNA termini for religation through noncovalent protein-DNA contacts.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
CGCTCATCGTCATCCTCGGCACCGT-3' and
5'-ACGGTGCCGAGGATGACGATG
AGCGCATTGTTAGATTTCA-3', respectively. A
second 40-base single-stranded oligonucleotide corresponding to
residues 1072-1111 of the MLL oncogene (28, 29) and its complementary oligonucleotide also were synthesized. The sequences of
the top and bottom strands were
5'-GCCTGGGTGACAAAGC
AAAACACTGTCTCCAAAAAAAATT-3' and
5'-AATTTTTTTTGGAGACAGTG
TTTTGCTTTGTCACCCAGGC-3', respectively. Points
of topoisomerase II-mediated cleavage in both sequences are denoted by
arrows. Single-stranded oligonucleotides containing a tetrahydrofuran
abasic site analog or a deoxyuridine residue were prepared in a similar
manner utilizing corresponding phosphoramidites obtained from Glen
Research Corp. (Sterling, VA). Single-stranded oligonucleotides were
labeled with [32P]phosphate on their 5'-termini with T4
polynucleotide kinase, purified by electrophoresis in a 7 M
urea, 14% polyacrylamide gel, visualized by UV shadowing, excised, and
eluted using the Qiagen extraction protocol. Complementary
oligonucleotides were annealed by incubating equimolar amounts of each
at 70 °C for 10 min and cooling to 25 °C (29).
was expressed and purified from Saccharomyces
cerevisiae as described previously (29, 30). DNA cleavage was
monitored as described previously (29). Reaction mixtures contained 100 nM oligonucleotide in 19 µl of cleavage buffer (10 mM Tris-HCl, pH 7.9, 0.1 mM EDTA, 100 mM KCl, and 2.5% glycerol) that contained 5 mM
MgCl2. Cleavage was initiated by the addition of 1 µl of
human topoisomerase II
(225 nM final concentration).
Reactions were incubated at 37 °C for 10 min (unless stated
otherwise) and stopped by the addition of 2 µl of 10% SDS followed
by 1.5 µl of 250 mM EDTA. DNA cleavage products were digested with proteinase K, precipitated with ethanol, and resolved by
electrophoresis in 7 M urea, 14% polyacrylamide gels.
Reaction products were visualized and quantified using a Molecular
Dynamics PhosphorImager system. Levels of DNA cleavage were
calculated relative to that obtained with the wild-type substrate.
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
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Fig. 1.
Model for positioning the DNA termini for
topoisomerase II-mediated religation. The 5'-DNA termini are
properly positioned for religation within the topoisomerase II cleavage
complex by covalent interactions with the enzyme rather than by base
pairing between the single-stranded cohesive ends (23) (shown at
left). The mechanism by which the 3'-DNA termini are
correctly aligned is unknown. Three possibilities are shown at
right. The ends may be positioned by base pairing with the
opposite DNA strand, by base stacking with the adjacent residue, or by
noncovalent interactions with the enzyme.
Because the enzyme does not form covalent bonds with the 3'-DNA termini, the basis for the alignment of the 3'-ends within the cleavage complex is not apparent. Three major possibilities exist (Fig. 1). First, the 3'-termini may be positioned for religation by base pairing to their complementary DNA strands. In support of this possibility, the 3'-terminal residues are located within the duplex portion of the cleaved helix following scission (18). Second, the 3'-termini may be positioned for religation by base stacking to their adjacent residues. In some cases, the energies of base stacking interactions approach those of base pairing (31). Third, the 3'-termini may be positioned by noncovalent interactions with topoisomerase II. This possibility is consistent with modeling studies (based on the crystal structure of yeast topoisomerase II) and mutagenesis experiments, which suggest that there are interactions between specific amino acids and the 3'-termini generated by cleavage (32, 33).
To distinguish between the above, the ability of human topoisomerase
II to religate a series of oligonucleotide substrates with altered
base pairing or base stacking at their 3'-DNA termini was determined.
The strategy underlying these religation experiments is as follows. If
the 3'-DNA termini are positioned primarily by base pairing or base
stacking, any modification that disrupts these interactions should
significantly decrease the rate of religation mediated by topoisomerase
II. In contrast, if the 3'-DNA termini are positioned primarily by
noncovalent interactions between the enzyme and the terminal base, only
modifications that remove or alter this base should inhibit religation.
Modifications that disrupt base pairing or base stacking without
affecting the 3'-terminal base should have marginal, if any, effects.
Cleavage and Religation of Substrates Containing a Single DNA
Lesion--
The initial sequence utilized for cleavage and religation
studies was a double-stranded 40-mer derived from plasmid pBR322 (18,
27). This sequence contained a single strong cleavage site for
topoisomerase II. The central portion of the oligonucleotide (with
points of cleavage denoted by arrows) is shown in Fig.
2. The nucleotide at the 1 position
relative to the point of cleavage becomes the 3'-terminal residue
following scission. The nucleotide at the +5 position on the opposite
strand is the residue that base pairs with the 3'-terminal base. To
disrupt base pairing of the 3'-terminus without precluding protein
interactions with the terminal base, an abasic site or a mismatched
base was placed at the +5 position of the oligonucleotide. To disrupt
both base pairing and potential protein interactions with the
3'-terminal base, an abasic site or a mismatched base was placed at the
1 position.
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As a prelude to religation studies, the ability of human topoisomerase
II to cleave the modified oligonucleotide substrates was examined
(Fig. 2). Consistent with previous studies (23, 29, 34), the
incorporation of an abasic site or a base mismatch immediately outside
the points of DNA cleavage decreased equilibrium levels of scission
(Fig. 2). However, even in the most dramatic case (
1 AP), levels of
scission were still high enough to reproducibly monitor rates of religation.
Fig. 3 depicts religation mediated by
human topoisomerase II for the top and bottom strands
(left and right panels, respectively) of the
pBR322 oligonucleotide substrate. Similar results were obtained for
both strands. In all cases, rates of religation for oligonucleotides
modified at the +5 position (either abasic sites or uracil mismatches)
were comparable to or faster than that of wild-type. This finding
indicates that base pairing is not used to align the 3'-termini for
religation.
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In marked contrast to the results observed with the +5 modifications,
the placement of an abasic site at the 1 position dramatically decreased the rate of religation. The presence of a uracil at the
1
position (which still allows base stacking (35, 36) but has the
potential to alter protein-DNA interactions) also diminished the
religation rate, albeit to a lesser extent than that observed with
substrates that lacked a
1 base. Taken together, these results
indicate that the presence of the base at the
1 position is critical
to the alignment of the 3'-DNA termini. However, they cannot
distinguish whether the termini are positioned by base stacking
interactions or by noncovalent topoisomerase II-DNA interactions.
Cleavage and Religation of Substrates Containing Two DNA
Lesions--
The experiments described above have one potential
caveat. Because the initial amount of scission observed with the 1
abasic site oligonucleotides was low (~10% of that for the wild-type substrate), it is possible that religation of these modified
oligonucleotides does not completely reflect the capabilities of the
type II enzyme. Therefore, a second abasic site was incorporated into
the pBR322 substrate to increase the starting level of DNA cleavage.
This second lesion was located within the 4-base cleavage overhang at
the +2 position (Fig. 4). Previous work
indicates that the incorporation of abasic sites between the points of
cleavage stimulates topoisomerase II-mediated DNA scission without
affecting rates of religation (23). As seen in Fig. 4, following the
inclusion of a +2 lesion in the top strand, levels of cleavage of the
1 abasic site oligonucleotide approached that of wild-type. Cleavage of a comparable +5,+2 bottom strand abasic substrate exceeded that of
the unmodified substrate.
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Similar to results obtained with the single lesion substrates, the
oligonucleotide that eliminated base pairing without removing the
3'-terminal base (i.e. the +5,+2 abasic substrate) displayed wild-type rates of religation (Fig.
4).1 Furthermore, the ability
of topoisomerase II to religate the oligonucleotide that eliminated
potential base stacking or protein interactions with the 3'-terminal
base (i.e. the 1,+2 substrate) was severely inhibited
(Fig. 4).2
To confirm the results found with the pBR322 substrate, cleavage and
religation of a second oligonucleotide was characterized (Fig.
5). This second substrate was derived
from a region of the MLL oncogene located proximal to a
leukemic breakpoint at chromosomal band 11q23 (28, 29). Once again,
oligonucleotides included two abasic sites to avoid potential problems
associated with the poor cleavage of single lesion substrates.
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Cleavage levels of both the +5,+2 and 1,+4 dual abasic
oligonucleotides exceeded that of wild-type (Fig. 5). As above,
religation of the 3'-DNA terminus appeared to be unaffected by the loss
of base pairing in the +5,+2 abasic substrate. However, religation was
drastically impaired when the 3'-base was absent in the
1,+4 abasic
substrate (Fig. 5). Similar results were observed for the top strand
3'-terminus when corresponding +5,+2 and
1,+4 oligonucleotides were
employed (not shown).
Effects of the 3'-Terminal Base on the DNA Cleavage/Re-ligation Equilibrium of Topoisomerase II-- The above experiments provide strong evidence that the 3'-terminal base is important for topoisomerase II-mediated DNA religation. However, the poor rates of religation observed for substrates that lacked this base were determined under conditions in which topoisomerase II catalyzed a unidirectional rejoining event. Therefore, an "approach to equilibrium" experiment was carried out to determine whether the lack of a 3'-terminal base also impairs religation under conditions in which topoisomerase II catalyzes a complete DNA cleavage/religation cycle.
The time required for topoisomerase II to reach its cleavage/religation
equilibrium reflects both the rates of cleavage and religation. Under
normal conditions, the rate of religation appears to be limiting (37).
Therefore, if the loss of the 3'-terminal base inhibits DNA religation,
the time it takes for the enzyme to establish a DNA cleavage/religation
equilibrium should be considerably longer than required for the
comparable wild-type substrate. As seen in Fig.
6, human topoisomerase II establishes
an equilibrium with the wild-type pBR322 oligonucleotide within 2 min.
A similar time to establish equilibrium was observed for the +5,+2
abasic pBR322 oligonucleotide, which disrupts base pairing without
removing the 3'-terminal base and displays wild-type rates of
religation (Fig. 4). In contrast, when the
1,+2 abasic
oligonucleotide (which eliminates the 3'-terminal base and displays
dramatically lower rates of religation (Fig. 4)) was employed, the
enzyme had yet to reach equilibrium by 20 min. This finding supports
the conclusion that the elimination of the 3'-terminal base impairs the
religation activity of topoisomerase II.
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Effects of 3'-Terminal Base Stacking on Topoisomerase II-mediated Religation-- The above results establish the importance of the 3'-terminal base in topoisomerase II-mediated DNA religation and rule out the requirement for terminal base pairing in this process. However, they do not address the potential contributions of base stacking or protein-DNA interactions in aligning the 3'-terminal residue for religation. A prominent role for base stacking seems unlikely, because all of the cleavage substrates used in the present study contain terminal thymine-guanine sequences. Of the possible nearest neighbors in DNA, thymine-guanine steps exhibit one of the weaker base stacking energies (31, 35).
The above notwithstanding, an additional religation experiment was
carried out to determine directly whether the 3'-DNA terminus is
aligned for topoisomerase II-mediated re-ligation by base stacking interactions. This experiment utilized an oligonucleotide substrate that replaced the thymine at the 2 position with an abasic site. This
substitution eliminates base stacking between the 3'-terminal residue
and its nearest neighbor, but preserves terminal base pairing and
potential interactions with the enzyme.
As seen in Fig. 7, human topoisomerase
II cleaved the
2 abasic substrate with an efficiency that was
similar to that of wild-type. Rates of DNA religation observed for the
abasic oligonucleotide also were comparable with the unmodified
sequence. This finding argues strongly against an important role for
base stacking in aligning the 3'-DNA termini for religation.
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In conclusion, the DNA religation activity of topoisomerase II is
critical to its physiological functions and its role as a target for
anticancer agents (4-6, 8, 12-15). Yet, the mechanism of this process
is not completely understood. A previous study demonstrated that the
enzyme utilizes covalent protein-DNA interactions to align the 5'-DNA
termini for religation (23). However, because topoisomerase II does not
form covalent bonds with the 3'-termini, it was not clear how these
unattached ends are positioned correctly for DNA religation. The
present work indicates that efficient religation requires the presence
of the 3'-terminal base. The proper alignment of this base does not
depend on either interstrand base pairing or intrastrand base stacking
interactions. Based on these findings, we propose that the 3'-termini
are properly positioned for DNA religation by noncovalent contacts
between topoisomerase II and the terminal base.
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ACKNOWLEDGEMENTS |
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We thank to Dr. P. S. Kingma for helpful discussions and to Dr. J. M. Fortune and K. D. Bromberg for critical reading of the manuscript.
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FOOTNOTES |
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* This work was supported by Grants GM33944 and GM53960 from the National Institutes of Health.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.
§ Trainee under National Institutes of Health Grant 5 T32 CA09385.
To whom correspondence should be addressed: Dept. of
Biochemistry, 654 Robinson Research Bldg., Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: 615-322-4338; Fax: 615-343-1166; E-mail: osheron@ctrvax.vanderbilt.edu.
Published, JBC Papers in Press, March 16, 2001, DOI 10.1074/jbc.M100197200
1 For all oligonucleotides that contained dual abasic lesions, rates of religation were determined for corresponding substrates that contained single +2 abasic sites (pBR322 sequences) or +4 abasic sites (MLL sequences). In all cases, rates were comparable with those of the wild-type oligonucleotides.
2 The DNA religation assays used for these experiments were based on trapping a kinetically competent topoisomerase II-DNA cleavage complex formed in the presence of CaCl2. Comparable results were obtained in parallel experiments that established DNA cleavage/re-ligation equilibria in the presence of MgCl2 and induced religation by lowering the reaction temperature to 0 °C.
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