From the Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207
Received for publication, December 4, 2002
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ABSTRACT |
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The effect of DNA interstrand cross-links
(cross-links) on DNA replication was examined with a
cell-free SV40 origin-dependent DNA replication system. A
defined template DNA with a single psoralen cross-link and the SV40
origin of replication was replicated by HeLa cell-free extract in the
presence of SV40 large T antigen. The psoralen cross-link inhibited DNA
replication by terminating chain elongation at 1-50 nucleotides before
the cross-linked sites. The termination of DNA replication by the
cross-links mediated the generation of double strand breaks near the
cross-linked sites. These results are the first biochemical
evidence of the generation of double strand breaks by DNA replication.
DNA interstrand cross-links
(cross-links)1 are unique DNA
damage because the two complementary strands of duplex DNA are
covalently linked through DNA lesions across the strands. DNA
replication and transcription are strongly inhibited by cross-links
because the two strands of duplex DNA cannot be separated, and thus
cross-links are highly cytotoxic (1). Cross-links are induced by
commonly used chemotherapeutic agents, such as melphalan and cisplatin; however, very little is known about how cross-links affect on DNA
replication or transcription at molecular level (2).
Cross-links are also challenging to DNA repair, because most DNA repair
systems use the complementary strand to restore the genetic information
after removal of DNA lesions from one strand of the duplex (3). The
molecular mechanism of cross-link repair in mammalian cells remains to
be elucidated. Genetic data implicated the involvement of XPF·ERCC1
complex, Rad51 paralogs (XRCC2, XRCC3, Rad51B, C, and D), and other
double strand break (DSB) repair proteins because mutant cells
defective in these factors are highly sensitive to DNA cross-linking
agents such as mitomycin C (1, 4). XRCC2 (5) and XRCC3 (6) are involved
in DNA double strand break repair by recombination. Recent biochemical
data demonstrated that the Rad51 paralogs modulate Rad51-catalyzed DNA
strand exchange (7, 8). The XPF·ERCC1 complex is a
cross-link-specific 3' to 5' exonuclease (9) and is required for
targeted homologous recombination as well (10, 11). In the cross-link
repair reaction dependent on the XPF·ERCC1 complex and recombination
machinery, DNA strand breaks may be requisite for XRCC2 and XRCC3 to
participate in the cross-link repair reaction, and a 3' end is needed
for the 3' to 5' exonuclease activity of the XPF·ERCC1 complex.
However, how these DNA breaks are generated and what proteins are
required for generation of the breaks are not understood.
Interestingly, DNA replication-dependent double strand
breaks have been detected in mammalian cells after treatment of the
cells with DNA cross-linking agents (12). Thus double strand breaks
could be an important intermediate in cross-link repair in mammalian
cells, because these breaks provide a 3' end near the cross-linked site
for the processing of the cross-link by the 3' to 5' exonuclease
activity of the XPF·ERCC1 complex to generate an appropriate
substrate for homologous recombination. It is also reported that DNA
replication is required to elicit a cell cycle delay response to
cross-link in mammalian cells (13). These data strongly implicate a
crucial role of DNA replication in cross-link repair in mammalian cells.
To study the effect of cross-links on DNA replication, a cell-free SV40
ori-dependent DNA replication system (14) was used. DNA replication was inhibited by the psoralen cross-links and mediated
formation of double strand breaks near the cross-linked sites. These
DNA replication-mediated double strand breaks are likely the
intermediates in cross-link repair reactions in human cells.
Enzymes and Oligonucleotide--
Restriction enzymes, T4
polynucleotide kinase, and calf intestinal alkaline phosphatase were
purchased form New England BioLabs (Beverly, MA). T4 DNA polymerse and
T4 DNA ligase to prepare substrate DNA were purchased from Roche
Molecular Biochemicals. SV40 large T antigen was purchased from
Molecular Biology Resources Inc. (Milwaukee, WI). A 13-mer
oligonucleotide (5'-GCTCGGTACCCGG-3') containing a furan-side psoralen
mono-adduct (MA) was a generous gift from Dr. John Hearst at Cerus
Corporation (Concord, CA).
Preparation of Substrate DNA--
A 350-bp fragment containing
the SV40 origin of replication was isolated from pcDNA 3.1 (from
Invitrogen) and subcloned at the EcoRV site of pIBI25
plasmid DNA to generate pEV. Using a single-stranded pEV DNA as
template, a covalently closed circular-defined substrate DNA was
prepared by second strand synthesis with T4 DNA polymerase and T4 DNA
ligase using a 13-mer primer containing a single furan-side psoralen
mono-adduct (15). The reaction products were then digested by
KpnI restriction endonuclease to eliminate non-damaged DNA.
The presence of a psoralen mono-adduct or cross-link at the 5'-TA-3'
site in the middle of the KpnI recognition site completely
inhibits digestion by KpnI (16, 17). After KpnI-digestion, the covalently closed circular DNA was
purified by CsCl gradient centrifugation, and the
mono-adduct-containing DNA was irradiated with UVA to convert
the mono-adduct to cross-link (15). The psoralen cross-link is located
at a 205 nt away from the SV40 origin of replication in the pEV plasmid
(Fig. 1). A substrate without SV40 origin of replication was prepared
by the same method except using a single-stranded pIBI25 DNA as template.
Preparation of Nuclear Extract--
Exponentially growing HeLa
S3 cells (10 liters) were purchased from National Cell Culture
Center. Nuclear extract was prepared following the method described in
Dignam et al. (18). The nuclear extract was dialyzed against
hypotonic buffer (20 mM HEPES-KOH, pH 7.8, 5 mM
KCl, 0.1 mM EDTA, 1.5 mM MgCl2, 1 mM dithiothreitol (DTT), and 15% glycerol) using
micro-dialyzer (Pierce) before DNA replication assay.
DNA Replication Assay--
Template DNA (25-100 ng) was
replicated with 40 µg of cell-free extract in the presence of
purified SV40 large T antigen (1 µg) by incubating at 30 °C for
the indicated times in 12.5 µl of reaction buffer containing 30 mM HEPES-KOH, pH 7.8, 7 mM MgCl2, 4 mM ATP, 200 µM of NTPs, 100 µM
of dNTPs with [ Determination of Replication Termination Sites--
The
replicated DNA was digested with NcoI restriction enzyme at
37 °C for 1 h and analyzed on a 4% sequencing gel. The
replicated non-damaged pEV DNA was digested with NcoI and
KpnI and used as a marker. Leading strand synthesis
generates a 103-nt fragment, and lagging strand synthesis generates a
99-nt fragment.
Detection of Double Strand Breaks--
Replicated DNA was
digested with NcoI restriction enzyme at 37 °C for 1 h and analyzed on a 2% agarose gel. After drying, the gel was exposed
and analyzed by phosphorimaging (Molecular Dynamics). If DSBs
occur, fragments shorter than full-length pEV DNA will be detected
because NcoI digests pEV DNA once. Reaction products with a
substrate DNA without the SV40 origin of replication were digested with
EcoRV restriction enzyme.
Mapping of Incision Sites at DSB Ends--
The substrate with a
XL was replicated for 4 h. After digestion with NcoI,
the reaction products were separated on a 2% agarose gel, and the
short fragment released was isolated from the agarose gel. One-half of
the DNA was dephosphorylated and then labeled with 32P
using T4 polynucleotide kinase. The isolated DNA before and after
phosphorylation by T4 polynucleotide kinase was analyzed on a 4%
sequencing gel. The replicated non-damaged pEV DNA was digested by
NcoI with KpnI, SmaI,
BamHI, XbaI, SalI, PstI, or XhoI and used as markers. Each double-digestion gives
size markers for lagging and leading strand synthesis.
Inhibition of DNA Replication by a Psoralen Cross-link in
Vitro--
A psoralen interstrand cross-link was placed 205 nt from
the SV40 origin of replication (Fig.
1A) in the pEV plasmid. This template DNA was incubated with 40 µg of cell-free extract prepared from HeLa cells in the presence of [ DNA Replication-mediated Generation of Double Strand Breaks Near
Cross-linked Sites--
Having established that DNA replication is
inhibited by the psoralen cross-links, I next examined whether DSBs are
induced during DNA replication reaction at the cross-link sites. After the replication reaction, the DNA was digested with NcoI and
analyzed on a 2% agarose gel (Fig. 3). A
short fragment whose size is similar to the
NcoI/KpnI fragment of pEV was detected (Fig.
3A, lanes 1 and 3). Because the
fragment was not generated before digestion with NcoI (data
not shown), the DSBs should have occurred near the KpnI
site, namely, near the cross-link site. Importantly, both the SV40
origin of replication (SV40 ori) and the SV40 Tag are requisite for the
induction of the DSB (Fig. 3B). Omission of rNTPs and/or
dNTPs also abolishes generation of DSBs (data not shown).
Interestingly, a much lower level of DSB was detected with a template
DNA containing a psoralen mono-adduct (MA) (Fig. 3A, lane 2; see the graph next to the
gel), even though the mono-adduct was just as effective as
the cross-link in the inhibition of replication (Fig. 2). The
generation of DSBs reached a plateau after 4 h (Fig. 3C), presumably because of the competition between the
ongoing DNA replication and cross-link repair.
I also determined the incision sites of DSBs on the template strand and
whether the incision occurs before or beyond the cross-linked site
relative to the direction of the movement of a replication fork. The
short fragments generated by NcoI-digestion (indicated by
arrows in Fig. 3) were isolated from the agarose gel, and
the fragments were labeled by T4 polynucleotide kinase after
dephosphorylation. Because the template strands are not labeled in the
replication reaction, a new fragment after the kinase reaction most
likely represents an incised fragment from the template strand. I
confirmed that DSBs were generated near the cross-link because only the same sizes of the fragments as the replication termination fragments (see Fig. 2B, lane 3) were found in the isolated
short fragment (Fig. 4, lane
1). A new fragment was not detected after the kinase reaction
(Fig. 4, lane 2), indicating that the incision site(s) on
the template strand to generate DSBs were similar in size to the
termination fragments. These data suggest that incisions on the
template strands during the generation of DSBs occur right across the
replication termination sites, i.e. before the cross-link relative to the direction of the movement of a replication fork. The
products from a reaction conducted under the same conditions except
using non-radioactive dNTPs, which were isolated from a 2% agarose gel
after digestion with NcoI and labeled by T4 PNK after
dephosphorylation, gave similar results (data not shown). I conclude
that DSBs are generated near the cross-link site during DNA
replication. This is the first demonstration using a defined substrate
that DNA replication generates a DSB at or near a cross-link.
Little is known about the molecular mechanism of repair of DNA
interstrand cross-links in humans. Based on the genetic data with DNA
cross-linking agent-hypersensitive mutant cell lines, it has been
proposed that a structure-specific endonuclease XPF·ERCC1 complex (4)
and DSB repair proteins, Rad51 paralogs (1), and BRCA2 (19) play
important roles in cross-link repair in mammalian cells. In addition,
two recent findings suggest a crucial role of DNA replication in
cross-link repair in mammalian cells. Hartley and co-workers (12)
showed the induction of DSBs in dividing nitrogen-mustard-treated
Chinese hamster ovary cells, but not in confluent cells, using
pulsed-field gel electrophoresis. Grompe and co-workers (13)
demonstrated that psoralen cross-links are not repaired in
G1 or G2 phase of the cell cycle until the subsequent S phase. However, there is no direct evidence that DNA
replication mediates formation of DSBs at or near cross-link sites.
This report is the first biochemical demonstration of the link between
DNA replication and cross-link repair. Based on the data presented
here, I propose a molecular mechanism of cross-link repair in humans
(Fig. 5). Three major steps will be
considered in cross-link repair in humans: (1) generation of a DSB at
or near a cross-link site, (2) unhooking of the cross-link, and (3) processing of the DSB and the unhooked gapped DNA. DNA replication is
inhibited near the cross-link sites probably for two reasons: one is
due to the inability of the two strands to be unwound and another is
because of the physical blockage to polymerase progression by the DNA
lesions on each of the strands. A stalled DNA polymerase generates a
unique DNA structure, which is a substrate for a structure-specific endonuclease to incise one of the template strands. The result is a
generation of a double strand break at one side of the growing fork and
a gap on the other side. If an incision occurs on a template for
leading strand synthesis, a 3' end to the cross-link will be generated.
The 3' to 5' exonuclease activity of XPF·ERCC1 complex will unhook
the cross-link. After unhooking of the cross-link, the DSB and the gap
are repaired by DSB repair. A lesion left on one strand after unhooking
of the cross-link will be repaired by nucleotide excision
repair.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
-32P]dATP (6000 Ci/mmol;
PerkinElmer Life Sciences), 40 mM creatine phosphate, and 1.0 µg of creatine phosphokinase. After the reaction, DNA was deprotenized with proteinase K/SDS, extracted with
phenol/chloroform and then purified by ethanol precipitation. The
product DNA was resuspended in 10 µl of TE (10 mM
Tris-Hcl (pH 8.0) and 1 mM EDTA) and used for the
various assays described below.
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
-32P]dATP and 1 µg of SV40 large T antigen. The incorporation of [32P]dAMP by DNA replication was greatly diminished by
the presence of the cross-link (80-90% inhibition of the
incorporation of 32P in acid-insoluble DNA compared with
the non-damaged template; data not shown). To determine the DNA
replication termination sites by the cross-links, DNA from the
replication reaction was digested with NcoI restriction
enzyme, which cuts the template DNA once in the middle of the SV40 ori
(Fig. 1A), and then analyzed on a 4% sequencing gel (Fig.
2). Several fragments (lane 3,
bracket) appeared only after NcoI digestion
(compare lanes 2 and 3). The size of the largest
fragment was shorter than the NcoI/KpnI fragment of the leading strand synthesis (lane 1, upper
arrow), and the others were shorter than the
NcoI/KpnI fragment of the lagging strand
synthesis (lane 1, lower arrow) from the
replicated non-damaged pEV DNA used as a marker. Using a template with
a furan-side psoralen mono-adduct at the same position as the
cross-link (on the template strand for the leading strand synthesis) as
control (lanes 4 and 5), the largest fragment
could be the result of the termination at one nucleotide before the
cross-link on the leading strand synthesis (lane 7), and the
others were the results of terminations before the cross-link site both
from leading and lagging strand synthesis. These data demonstrate that
DNA replication was terminated at multiple sites before the
cross-links.
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Fig. 1.
Key restriction sites on pEV DNA.
A, location of a psoralen cross-link in the template DNA. A
psoralen interstrand cross-link (XL) is located at the
5'-TA-3' site in the middle of KpnI site
5'-GGTACC-3'. The NcoI site is in the middle of
the SV40 origin of replication (SV40 ori). The bold arrows
represent the leading strand synthesis, and the dashed
arrows represent the lagging strand synthesis. After the
replication reaction, a termination site of DNA chain elongation can be
detected on a sequencing gel after NcoI digestion. If a DSB
occurs near a cross-link site, a short fragment with a similar length
to the NcoI-KpnI fragment (~ 200 bp) will be
detected on an agarose gel. B, restriction sites near the
cross-link. SmaI, BamHI, XbaI,
SalI, PstI, and XhoI sites are located
at 3, 10, 15, 22, 24, and 39 nt away from the cross-link site toward
the SV40 ori, respectively. EcoRI site is located 10 nt from
the cross-link away from the SV40 ori.
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Fig. 2.
Inhibition of DNA replication by
a psoralen cross-link. A template DNA (25 ng) was replicated with
40 µg of cell-free extract in the presence of purified SV40 large T
antigen (1 µg) by incubating at 30 °C for 3 h in 12.5 µl of
replication reaction buffer. After the DNA replication reaction, the
DNA was digested with NcoI and the DNA before (lanes
2, 4, and 6) and after the
NcoI-digestion (lanes 3, 5, and
7) were analyzed on a 4% sequencing gel. The
bracket in lanes 3 and 7 shows the
multiple termination sites of DNA chain elongation by the cross-link.
It is noted that a psoralen mono-adduct gave a single termination site,
one nucleotide before the adduct (the arrow in lane
5). A replicated non-damaged DNA was digested with NcoI
and KpnI and a part of the reaction was used as a size
marker (lane 1). The upper arrow in lane
1 shows the product of leading strand synthesis, and the
lower arrow shows the product of lagging strand synthesis.
The higher molecular weight fragments indicated by asterisks
appeared to be the results of replication of the other half of the pEV
molecule (left side of the SV40 ori in Fig. 1). Lanes
4 and 5, a template DNA with a MA; lanes 2,
3, 6, and 7, a template DNA with a XL.
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Fig. 3.
Induction of DSB at a psoralen
interstrand cross-link by DNA replication. A, interstrand
cross-link-specific induction of DSB. A psoralen interstrand cross-link
(XL, lane 1) or a psoralen mono-adduct
(MA, lane 2) containing DNA (25 ng) was
replicated as described in the legend to Fig. 2. After the reaction,
the DNA was digested with NcoI and analyzed on a 2% agarose
gel. About 2 and 0.1% of the total 32P incorporated were
found in the short fragments in lanes 1 and 2,
respectively, and these values were depicted as a graph next
to the gel. The short fragment in lane 2 was
detected only after a longer exposure (data not shown). A non-damaged
DNA was replicated with the same way and digested with NcoI
and KpnI, and a part of the reaction was used as a marker
(lane 3, NcoI/KpnI). It is noted that
if the generation of DSB is not associated with DNA synthesis, the DSB
cannot be detected under the assay conditions used. B, SV40
origin of replication and SV40 large T antigen are required for
generation of DSB at the cross-link site. A cross-link containing DNA
(100 ng) was incubated in the presence (lanes 5 and
7) and absence of SV40 large T antigen (lanes 4 and 6) and analyzed as described above. In lanes
4 and 5 the substrate with the SV40 ori was incubated
for 2 h, and the DNA was digested with NcoI. In lanes 6 and 7, the substrate without the SV40 ori was
incubated for 4 h, and the DNA was digested with EcoRV
to detect DSBs. The induction of DSB required both SV40 ori and SV40
large T antigen. No fragment was detected after a 2 day-exposure to
phosphorimaging screen in lanes 4, 6, and
7. C, saturation of the generation of DSBs. A
cross-link containing DNA (100 ng) was replicated, and the aliquots
were withdrawn from the reaction mixture at the indicated time points
and resolved on 2% agarose gels. The efficiency of the generation of
DSB was quantitated as described above, and average values of three
independent experiments were plotted as a graph next to the
gel. Bars represent the standard error.
Lanes 8 and 9, a cross-link containing DNA was
incubated for 6 h under replication conditions in the absence of
SV40 Tag. Lane 9 is a longer exposure of lane 8. Lanes 10-13, time course experiments. The
arrow shows the DSB product. Nearly all of the products were
replicated two rounds after 8 h incubation when non-damaged pEV
was used as template under the same conditions (data not shown).
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Fig. 4.
Mapping of the sites of DSB induced by
replication. The substrate with a XL was replicated for 4 h
as described in the legend to Fig. 2. After digestion with
NcoI, the reaction products were separated on a 2% agarose
gel, and the short fragment released was isolated from the gel.
One-half of the isolated DNA was dephosphorylated and then labeled with
32P by T4 polynucleotide kinase. The isolated DNA before
(lane 1) and after labeling (lane 2) was analyzed
on a 4% sequencing gel. The bracket indicates the mixture
of the termination sites of DNA replication (newly replicated strands,
lane 1) and the incision sites on the template strands
(lane 2). Replicated non-damaged DNA was digested by
NcoI plus KpnI (K), SmaI
(S), BamHI (B), XbaI
(X), SalI (SalI), PstI
(P), or XhoI and used as markers. Each
double-digestion gives size markers for lagging and leading strand
synthesis.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Fig. 5.
Proposed model for DNA replication-mediated
cross-link repair in humans. DNA replication encounters a
cross-link, and a DNA polymerase is stalled at the cross-linked site. A
Y-shape DNA structure will be formed. A specific endonuclease that
recognizes this DNA structure generates a nick in either of the
template strands resulting in induction of a DSB near the cross-linked
site. The cross-linked strands are unhooked by the 3' to 5' exonuclease
activity of XPF·ERCC1 complex. A gap generated by XPF·ERCC1 complex
is filled either by homologous recombination using a homologous pair or
by an error-free translesion DNA synthesis mediated by an unidentified
polymerase. The DSB is repaired by homologous recombination, probably
by a break-induced repair using a sister chromatid as template, and the
collapsed replication fork is restored.
A major role of DNA replication in cross-link repair will be formation of a "Y-shape" DNA structure at a stalled site. The Y-shape structure contains two junctures with different polarity. One in lagging strand synthesis is suitable for the FEN-1 family of nucleases (20) and another in leading strand synthesis is a good substrate for XPF·ERCC1 complex (21-24) and Mus81 nuclease (25). An incision in either juncture results in a formation of a DSB; however, the latter juncture will be preferable because an incision at this juncture will provide a 3' nick to a cross-link, which is further processed by the cross-link-unhooking exonuclease activity of XPF·ERCC1 complex (9). Identification of the corresponding nuclease in the generation of DSBs during DNA replication-mediated cross-link repair is under way. It will also be very interesting to examine whether a stalled DNA polymerase plays a direct role in recruiting an endonuclease to a cross-linked site.
Using a cell-free system without DNA replication, it has been shown
that psoralen cross-links induce an XPF·ERCC1- and
XRCC3-dependent DNA synthesis both in damaged and undamaged
DNA (homologous or heterologous DNA), and hMutS and XPF·ERCC1
complex are required to unhook psoralen cross-links during the DNA
synthesis in the absence of DNA replication (26, 27). Both reports
demonstrated "DNA repair synthesis" in damaged DNA in the presence
of exogenous DNA; however, it is not clear that the observed DNA
synthesis is the complete repaired product or a futile DNA repair
synthesis (9) because fully repaired fragments were not examined. It is
very interesting to examine the effect of DNA replication on cross-link
repair using the cell-free DNA replication system reported here.
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ACKNOWLEDGEMENTS |
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The author thanks Dr. John Hearst (Cerus Corporation) for the psoralen-modified oligonucleotides and Dr. Joyce Reardon (University of North Carolina at Chapel Hill, NC) for critical reading of the manuscript.
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FOOTNOTES |
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* This work is supported by the New Faculty Start-Up Award from Howard Hughes Medical Institute Research Resources Program and the Institutional Research Grant from the San Antonio Cancer Institute.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: Dept. of
Molecular Medicine, Inst. of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr., San Antonio, TX
78245-3207. Tel.: 210-567-7254; Fax: 210-567-7247; E-mail: besshot@uthscsa.edu.
Published, JBC Papers in Press, December 8, 2002, DOI 10.1074/jbc.M212323200
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ABBREVIATIONS |
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The abbreviations used are: cross-links, DNA interstrand cross-links; ori, origin of replication; XL, psoralen interstrand cross-link; DSB, double strand break; nt, nucleotide; MA, mono-adduct.
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