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Namespace Prefixes

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Statements

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n2:19713438
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n3:RelevantPaper n3:ReferencePaper n3:CitationPaper
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n6:0 n9:19713438 n10:10.1093%2Fnar%2Fgkp705 n11:0
bibo:cites
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PMC0
bibo:doi
10.1093%2Fnar%2Fgkp705
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_:vb5924958 _:vb5924910 _:vb5924872 _:vb5924895
Subject Item
_:vb5924872
rdf:type
n8:Section
dc:title
introduction
n8:contains
_:vb5924876 _:vb5924877 _:vb5924878 _:vb5924879 _:vb5924873 _:vb5924874 _:vb5924875 _:vb5924884 _:vb5924885 _:vb5924886 _:vb5924887 _:vb5924880 _:vb5924881 _:vb5924882 _:vb5924883 _:vb5924892 _:vb5924893 _:vb5924894 _:vb5924888 _:vb5924889 _:vb5924890 _:vb5924891
Subject Item
_:vb5924873
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ICLs covalently modify both strands of the DNA, thus preventing their separation and consequently blocking transcription, segregation and replication (>>1<<). ICL agents have been effectively used in anticancer chemotherapy, because their toxicity targets proliferating cells. Even though a variety of DNA adducts can be produced by cross-linking agents, their effective cytotoxicity is related
n3:mentions
n2:8781575
Subject Item
_:vb5924874
rdf:type
n3:Context
rdf:value
Even though a variety of DNA adducts can be produced by cross-linking agents, their effective cytotoxicity is related to their capability of forming ICLs (>>2<<). Due to the complexity of the ICL-induced DNA damage, repair machinery that simply excises the damaged DNA and then uses replication from a template for nucleotide replacement is inadequate. This has been well demonstrated in Escherichia
n3:mentions
n2:12437330
Subject Item
_:vb5924875
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n3:Context
rdf:value
has been well demonstrated in Escherichia coli and Saccharomyces cerevisiae, where components of nucleotide excision repair (NER), homologous recombination (HR) and translesion synthesis (TLS) are all required for adequate ICL repair (>>3<<,4). However, it is shown that a replication and recombination independent ICL repair machinery is active on transcribed DNA (5,6).
n3:mentions
n2:11516927
Subject Item
_:vb5924876
rdf:type
n3:Context
rdf:value
has been well demonstrated in Escherichia coli and Saccharomyces cerevisiae, where components of nucleotide excision repair (NER), homologous recombination (HR) and translesion synthesis (TLS) are all required for adequate ICL repair (3,>>4<<). However, it is shown that a replication and recombination independent ICL repair machinery is active on transcribed DNA (5,6).
n3:mentions
n2:11905724
Subject Item
_:vb5924877
rdf:type
n3:Context
rdf:value
However, it is shown that a replication and recombination independent ICL repair machinery is active on transcribed DNA (>>5<<,6).
n3:mentions
n2:11154259
Subject Item
_:vb5924878
rdf:type
n3:Context
rdf:value
However, it is shown that a replication and recombination independent ICL repair machinery is active on transcribed DNA (5,>>6<<).
n3:mentions
n2:12509472
Subject Item
_:vb5924879
rdf:type
n3:Context
rdf:value
Studies have proposed that among all the NER proteins only ERCC1 and XPF play a key role in ICL repair (>>7<<). The ERCC1 protein forms a highly conserved endonuclease heterodimeric complex with XPF (8) that stabilizes both proteins for their role in DNA repair (9,10). In mammalian cells, this structure-specific heterodimeric endonuclease
n3:mentions
n2:12202770
Subject Item
_:vb5924880
rdf:type
n3:Context
rdf:value
The ERCC1 protein forms a highly conserved endonuclease heterodimeric complex with XPF (>>8<<) that stabilizes both proteins for their role in DNA repair (9,10).
n3:mentions
n2:8197175
Subject Item
_:vb5924881
rdf:type
n3:Context
rdf:value
The ERCC1 protein forms a highly conserved endonuclease heterodimeric complex with XPF (8) that stabilizes both proteins for their role in DNA repair (>>9<<,10). In mammalian cells, this structure-specific heterodimeric endonuclease complex, ERCC1-XPF, is recruited by XPA to the damaged DNA site (11) to create a nick at the 5′ side of the helix-distorting lesion. A structure specific
n3:mentions
n2:8253090
Subject Item
_:vb5924882
rdf:type
n3:Context
rdf:value
The ERCC1 protein forms a highly conserved endonuclease heterodimeric complex with XPF (8) that stabilizes both proteins for their role in DNA repair (9,>>10<<). In mammalian cells, this structure-specific heterodimeric endonuclease complex, ERCC1-XPF, is recruited by XPA to the damaged DNA site (11) to create a nick at the 5′ side of the helix-distorting lesion. A structure specific
n3:mentions
n2:8253091
Subject Item
_:vb5924883
rdf:type
n3:Context
rdf:value
In mammalian cells, this structure-specific heterodimeric endonuclease complex, ERCC1-XPF, is recruited by XPA to the damaged DNA site (>>11<<) to create a nick at the 5′ side of the helix-distorting lesion.
n3:mentions
n2:11511374
Subject Item
_:vb5924884
rdf:type
n3:Context
rdf:value
A structure specific endonuclease, XPG, compliments ERCC1-XPF by nicking the DNA on the other side of the lesion, thus excising the damaged DNA (>>12<<). These endonucleases also cleave many DNA structures, including bubbles, stem–loops, splayed arms and flaps (13–15). Importantly, mammalian XPG mutants were shown to be less sensitive to ICL damage when compared to ERCC1 and XPF mutants
n3:mentions
n2:10197977
Subject Item
_:vb5924885
rdf:type
n3:Context
rdf:value
These endonucleases also cleave many DNA structures, including bubbles, stem–loops, splayed arms and flaps (13–>>15<<). Importantly, mammalian XPG mutants were shown to be less sensitive to ICL damage when compared to ERCC1 and XPF mutants (7,16) implying that ICL repair in mammals is different from ICL repair in lower eukaryotes, where both endonuclease
n3:mentions
n2:10320375 n2:9525876 n2:9013642
Subject Item
_:vb5924886
rdf:type
n3:Context
rdf:value
Importantly, mammalian XPG mutants were shown to be less sensitive to ICL damage when compared to ERCC1 and XPF mutants (>>7<<,16) implying that ICL repair in mammals is different from ICL repair in lower eukaryotes, where both endonuclease activities are necessary for efficient ICL repair (17).
n3:mentions
n2:12202770
Subject Item
_:vb5924887
rdf:type
n3:Context
rdf:value
Importantly, mammalian XPG mutants were shown to be less sensitive to ICL damage when compared to ERCC1 and XPF mutants (7,>>16<<) implying that ICL repair in mammals is different from ICL repair in lower eukaryotes, where both endonuclease activities are necessary for efficient ICL repair (17).
n3:mentions
n2:11027268
Subject Item
_:vb5924888
rdf:type
n3:Context
rdf:value
less sensitive to ICL damage when compared to ERCC1 and XPF mutants (7,16) implying that ICL repair in mammals is different from ICL repair in lower eukaryotes, where both endonuclease activities are necessary for efficient ICL repair (>>17<<).
n3:mentions
n2:11516927
Subject Item
_:vb5924889
rdf:type
n3:Context
rdf:value
Moreover, XPF patients’ cells were shown to proficiently process ICLs but failed to deal with mono-adducts via NER (>>18<<), suggesting that XPF functions in ICL repair in an NER independent manner.
n3:mentions
n2:11095693
Subject Item
_:vb5924890
rdf:type
n3:Context
rdf:value
The ERCC1-XPF endonuclease complex has been reported to cleave an artificial substrate on both sides of a crosslink lesion, flanking a single-stranded 3′ flap, induced by psoralen (>>19<<). Therefore the ERCC1-XPF endonuclease function was designated as the initiation of the strand breaks adjacent to, and on each side of, the lesion in one strand of the DNA during ICL repair, known as the unhooking step. However, this
n3:mentions
n2:10882712
Subject Item
_:vb5924891
rdf:type
n3:Context
rdf:value
However, this contradicts cellular findings that ICL-inducing agents cause the same increased level of DNA double-strand break (DSB) formation in ERCC1 and XPF mutant cells as in wild-type cells (>>16<<,20). These findings suggest that ERCC1-XPF functions after formation of the DSB. In addition to their role in NER and ICL repair, the ERCC1–XPF complex has been found to function in some sub-pathways of homology-directed DSB repair,
n3:mentions
n2:11027268
Subject Item
_:vb5924892
rdf:type
n3:Context
rdf:value
However, this contradicts cellular findings that ICL-inducing agents cause the same increased level of DNA double-strand break (DSB) formation in ERCC1 and XPF mutant cells as in wild-type cells (16,>>20<<). These findings suggest that ERCC1-XPF functions after formation of the DSB. In addition to their role in NER and ICL repair, the ERCC1–XPF complex has been found to function in some sub-pathways of homology-directed DSB repair, through
n3:mentions
n2:15199134
Subject Item
_:vb5924893
rdf:type
n3:Context
rdf:value
In addition to their role in NER and ICL repair, the ERCC1–XPF complex has been found to function in some sub-pathways of homology-directed DSB repair, through single-strand annealing, gene conversion and homologous gene targeting (21–>>24<<).
n3:mentions
n2:11000269 n2:17962301 n2:11707424 n2:11032822
Subject Item
_:vb5924894
rdf:type
n3:Context
rdf:value
The exact role of the ERCC1–XPF complex in ICL repair is still under debate (>>25<<), although most data suggest a link with HR, as discussed above.
n3:mentions
n2:18192062
Subject Item
_:vb5924895
rdf:type
n8:Section
dc:title
materials and methods
n8:contains
_:vb5924904 _:vb5924905 _:vb5924906 _:vb5924907 _:vb5924908 _:vb5924909 _:vb5924896 _:vb5924897 _:vb5924898 _:vb5924899 _:vb5924900 _:vb5924901 _:vb5924902 _:vb5924903
Subject Item
_:vb5924896
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12 cell lines were created following the electroporation of the SCneo vector into the parental AA8 and Rad51D1–/– 51D1 cells and isolation of individual clones as described earlier (Table 1) (>>26<<). The SQ20B human head and neck cancer cell line was obtained from ATCC. Table 1.
n3:mentions
n2:16055725
Subject Item
_:vb5924897
rdf:type
n3:Context
rdf:value
Cell lineGenotypeDefect / modificationOriginIC50 [MMC] (nM)IC50 [cisplatin] (nM)IC50 [melphalan] (nM)Reference51D1RAD51D−/−RAD51D knockoutAA8NDNDND(>>26<<)51D1SC.2,RAD51D−/−Integrated SCneo51D13.0797.860.23This study51D1SC.4recombination reporter (hygR)3.44116.10NDAA8wtwtOvary238.98ND6.94(35)AA8SN.
n3:mentions
n2:16055725
Subject Item
_:vb5924898
rdf:type
n3:Context
rdf:value
4recombination reporter (hygR)3.44116.10NDAA8wtwtOvary238.98ND6.94(>>35<<)AA8SN.10,wtIntegrated SCneoAA8275.05>1000NDThis studyAA8SN.
n3:mentions
n2:15944449
Subject Item
_:vb5924899
rdf:type
n3:Context
rdf:value
12recombination reporter (hygR)290.46>1000NDERCC1.17,wtIntegrated DRneoUV4DR7164.41>10006.97(>>22<<)ERCC1.21recombination reporter (hygR) + ERCC1 expressing vector164.70>1000NDirs1SFXRCC3−XRCC3−, deficient in HRAA81.36NDND(35)PEF7ERCC1−integrated DRneo recombination reporter (hygR) + empty vectorUV4DR71.4961.240.33(22)S8DN4wtIntegrated
n3:mentions
n2:17962301
Subject Item
_:vb5924900
rdf:type
n3:Context
rdf:value
12recombination reporter (hygR)290.46>1000NDERCC1.17,wtIntegrated DRneoUV4DR7164.41>10006.97(22)ERCC1.21recombination reporter (hygR) + ERCC1 expressing vector164.70>1000NDirs1SFXRCC3−XRCC3−, deficient in HRAA81.36NDND(>>35<<)PEF7ERCC1−integrated DRneo recombination reporter (hygR) + empty vectorUV4DR71.4961.240.33(22)S8DN4wtIntegrated DRneo recombination reporter (hygR)SPD8ND919.64ND(22)UV4DR7ERCC1−Integrated DRneo recombination reporter
n3:mentions
n2:15944449
Subject Item
_:vb5924901
rdf:type
n3:Context
rdf:value
reporter (hygR) + ERCC1 expressing vector164.70>1000NDirs1SFXRCC3−XRCC3−, deficient in HRAA81.36NDND(35)PEF7ERCC1−integrated DRneo recombination reporter (hygR) + empty vectorUV4DR71.4961.240.33(>>22<<)S8DN4wtIntegrated DRneo recombination reporter (hygR)SPD8ND919.64ND(22)UV4DR7ERCC1−Integrated DRneo recombination reporter (hygR)AA81.4577.610.40(22)V79ZwtwtLungNDND8.71(58)V-C8BRCA2−BRCA2−, deficient in
n3:mentions
n2:17962301
Subject Item
_:vb5924902
rdf:type
n3:Context
rdf:value
vector164.70>1000NDirs1SFXRCC3−XRCC3−, deficient in HRAA81.36NDND(35)PEF7ERCC1−integrated DRneo recombination reporter (hygR) + empty vectorUV4DR71.4961.240.33(22)S8DN4wtIntegrated DRneo recombination reporter (hygR)SPD8ND919.64ND(>>22<<)UV4DR7ERCC1−Integrated DRneo recombination reporter (hygR)AA81.4577.610.40(22)V79ZwtwtLungNDND8.71(58)V-C8BRCA2−BRCA2−, deficient in HRV79ZNDND0.08(59)V-C8+B2wtExpressing BRCA2 from
n3:mentions
n2:17962301
Subject Item
_:vb5924903
rdf:type
n3:Context
rdf:value
DRneo recombination reporter (hygR) + empty vectorUV4DR71.4961.240.33(22)S8DN4wtIntegrated DRneo recombination reporter (hygR)SPD8ND919.64ND(22)UV4DR7ERCC1−Integrated DRneo recombination reporter (hygR)AA81.4577.610.40(>>22<<)V79ZwtwtLungNDND8.71(58)V-C8BRCA2−BRCA2−, deficient in HRV79ZNDND0.08(59)V-C8+B2wtExpressing BRCA2 from
n3:mentions
n2:17962301
Subject Item
_:vb5924904
rdf:type
n3:Context
rdf:value
recombination reporter (hygR) + empty vectorUV4DR71.4961.240.33(22)S8DN4wtIntegrated DRneo recombination reporter (hygR)SPD8ND919.64ND(22)UV4DR7ERCC1−Integrated DRneo recombination reporter (hygR)AA81.4577.610.40(22)V79ZwtwtLungNDND8.71(>>58<<)V-C8BRCA2−BRCA2−, deficient in HRV79ZNDND0.08(59)V-C8+B2wtExpressing BRCA2 from
n3:mentions
n2:13576097
Subject Item
_:vb5924905
rdf:type
n3:Context
rdf:value
DRneo recombination reporter (hygR)SPD8ND919.64ND(22)UV4DR7ERCC1−Integrated DRneo recombination reporter (hygR)AA81.4577.610.40(22)V79ZwtwtLungNDND8.71(58)V-C8BRCA2−BRCA2−, deficient in HRV79ZNDND0.08(>>59<<)V-C8+B2wtExpressing BRCA2 from
n3:mentions
n2:11756561
Subject Item
_:vb5924906
rdf:type
n3:Context
rdf:value
reporter (hygR)SPD8ND919.64ND(22)UV4DR7ERCC1−Integrated DRneo recombination reporter (hygR)AA81.4577.610.40(22)V79ZwtwtLungNDND8.71(58)V-C8BRCA2−BRCA2−, deficient in HRV79ZNDND0.08(59)V-C8+B2wtExpressing BRCA2 from vectorV-C8NDND27.80(>>59<<
n3:mentions
n2:11756561
Subject Item
_:vb5924907
rdf:type
n3:Context
rdf:value
The amount of ssDNA was measured after 1-h post-treatment with HU/AraC by the alkaline DNA unwinding technique as described elsewhere (>>27<<,28).
n3:mentions
n2:15537835
Subject Item
_:vb5924908
rdf:type
n3:Context
rdf:value
The amount of ssDNA was measured after 1-h post-treatment with HU/AraC by the alkaline DNA unwinding technique as described elsewhere (27,>>28<<).
n3:mentions
n2:35744
Subject Item
_:vb5924909
rdf:type
n3:Context
rdf:value
unwinding were ended by neutralization by adding 1 ml NaH2PO4 to each well and the samples were sonicated for 15 se before the addition of SDS to a final concentration of 0.25% and storage in −20°C until elution as described elsewhere (>>27<<).
n3:mentions
n2:15537835
Subject Item
_:vb5924910
rdf:type
n8:Section
dc:title
results
n8:contains
_:vb5924956 _:vb5924957 _:vb5924952 _:vb5924953 _:vb5924954 _:vb5924955 _:vb5924948 _:vb5924949 _:vb5924950 _:vb5924951 _:vb5924944 _:vb5924945 _:vb5924946 _:vb5924947 _:vb5924940 _:vb5924941 _:vb5924942 _:vb5924943 _:vb5924936 _:vb5924937 _:vb5924938 _:vb5924939 _:vb5924932 _:vb5924933 _:vb5924934 _:vb5924935 _:vb5924928 _:vb5924929 _:vb5924930 _:vb5924931 _:vb5924924 _:vb5924925 _:vb5924926 _:vb5924927 _:vb5924920 _:vb5924921 _:vb5924922 _:vb5924923 _:vb5924916 _:vb5924917 _:vb5924918 _:vb5924919 _:vb5924912 _:vb5924913 _:vb5924914 _:vb5924915 _:vb5924911
Subject Item
_:vb5924911
rdf:type
n3:Context
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Use of the RAD51D−/− cells generated through a knockout approach in wild type CHO cells (>>29<<) provides a strong model system for DNA repair studies, as these isogenic mutants do not have the phenotypic complications associated with the random mutagenesis used to create other CHO DNA repair mutants.
n3:mentions
n2:16522646
Subject Item
_:vb5924912
rdf:type
n3:Context
rdf:value
Here, we transfected the SCneo recombination reporter (Figure 1A) (>>30<<) through electroporation into the RAD51D-defecient CHO cells, 51D1, and parental AA8 cell lines and isolated independent hygromycin-resistant clones stably carrying a single copy of the SCneo reporter; 51D1SC.
n3:mentions
n2:10517641
Subject Item
_:vb5924913
rdf:type
n3:Context
rdf:value
It has long been understood that ICL agents trigger HR in mammalian cells (>>31<<) and that recombination-defective cells show an extreme hypersensitivity to such cross-linkers (32,33).
n3:mentions
n2:954106
Subject Item
_:vb5924914
rdf:type
n3:Context
rdf:value
It has long been understood that ICL agents trigger HR in mammalian cells (31) and that recombination-defective cells show an extreme hypersensitivity to such cross-linkers (>>32<<,33). Similarly, it has been shown that ERCC1-defective cells are hypersensitive to cross-linkers (34) and that ERCC1 may play a role in ICL repair separate to that of its function in NER (16).
n3:mentions
n2:3106801
Subject Item
_:vb5924915
rdf:type
n3:Context
rdf:value
It has long been understood that ICL agents trigger HR in mammalian cells (31) and that recombination-defective cells show an extreme hypersensitivity to such cross-linkers (32,>>33<<). Similarly, it has been shown that ERCC1-defective cells are hypersensitive to cross-linkers (34) and that ERCC1 may play a role in ICL repair separate to that of its function in NER (16).
n3:mentions
n2:1922147
Subject Item
_:vb5924916
rdf:type
n3:Context
rdf:value
Similarly, it has been shown that ERCC1-defective cells are hypersensitive to cross-linkers (>>34<<) and that ERCC1 may play a role in ICL repair separate to that of its function in NER (16).
n3:mentions
n2:3919454
Subject Item
_:vb5924917
rdf:type
n3:Context
rdf:value
Similarly, it has been shown that ERCC1-defective cells are hypersensitive to cross-linkers (34) and that ERCC1 may play a role in ICL repair separate to that of its function in NER (>>16<<). Here, we confirm that both ERCC1- and HR-defective RAD51D–/– cells are hypersensitive to the cross-linkers mitomycin C, cisplatin and melphalan (Figure 2). We find that ERCC1 mutated cells are more sensitive to mitomycin C and cisplatin
n3:mentions
n2:11027268
Subject Item
_:vb5924918
rdf:type
n3:Context
rdf:value
This is likely depending on a separate role for the ERCC1 in repair of the intra-cross-links produced by mitomycin C and cisplatin that are repaired by NER (>>5<<,6). On the contrary to this, we find that RAD51D–/– and BRCA2-defective V-C8 cells are more sensitive to melphalan than the ERCC1-defective cells (Figure 1C), which confirms an earlier finding that XRCC3-defective cells are more sensitive
n3:mentions
n2:11154259
Subject Item
_:vb5924919
rdf:type
n3:Context
rdf:value
This is likely depending on a separate role for the ERCC1 in repair of the intra-cross-links produced by mitomycin C and cisplatin that are repaired by NER (5,>>6<<). On the contrary to this, we find that RAD51D–/– and BRCA2-defective V-C8 cells are more sensitive to melphalan than the ERCC1-defective cells (Figure 1C), which confirms an earlier finding that XRCC3-defective cells are more sensitive
n3:mentions
n2:12509472
Subject Item
_:vb5924920
rdf:type
n3:Context
rdf:value
and BRCA2-defective V-C8 cells are more sensitive to melphalan than the ERCC1-defective cells (Figure 1C), which confirms an earlier finding that XRCC3-defective cells are more sensitive than ERCC1-defective cells to this drug (>>35<<). These data support the differential use of DNA repair pathways when repairing different cross-link lesions.
n3:mentions
n2:15944449
Subject Item
_:vb5924921
rdf:type
n3:Context
rdf:value
Single-strand annealing (SSA), a non-conservative HR sub-pathway, does not produce a functional neoR gene (>>60<<). (B) Recombination frequency to G418 resistance after transient transfection of the pCMV3xnlsI-SceI vector. Resistance to G418 reflects a recombination event of either intrachromatid pairing or sister chromatid pairing but not SSA.
n3:mentions
n2:15252152
Subject Item
_:vb5924922
rdf:type
n3:Context
rdf:value
experiments in UV4DR7 (ERCC1 mutated) and ERCC1 complemented cells (ERCC1.17, ERCC1.21) or transfection with empty vector (PEF7), along with wild-type AA8 cells (AA8SN.10, AA8SN.12) or RAD51D targeted cells (51D1SC.2, 51D1SC.4) (>>26<<) as well as BRCA2-defective V-C8 cells and wild-type (V79Z) or BRCA2 complemented control (V-C8+B2) (59) following treatment with (A) mitomycin C (MMC) (B), cisplatin or (C) melphalan.
n3:mentions
n2:16055725
Subject Item
_:vb5924923
rdf:type
n3:Context
rdf:value
4) (26) as well as BRCA2-defective V-C8 cells and wild-type (V79Z) or BRCA2 complemented control (V-C8+B2) (>>59<<) following treatment with (A) mitomycin C (MMC) (B), cisplatin or (C) melphalan.
n3:mentions
n2:11756561
Subject Item
_:vb5924924
rdf:type
n3:Context
rdf:value
It is established that ICLs are converted into DSBs during repair in mammalian cells, although the extent of DSB formation varies widely between different crosslinkers (>>36<<). It has previously been demonstrated that the Mus81–Eme1 complex is involved in converting ICLs into DSBs (37) independently to the ERCC1–XPF endonuclease activity (16,20).
n3:mentions
n2:12202770
Subject Item
_:vb5924925
rdf:type
n3:Context
rdf:value
It has previously been demonstrated that the Mus81–Eme1 complex is involved in converting ICLs into DSBs (>>37<<) independently to the ERCC1–XPF endonuclease activity (16,20).
n3:mentions
n2:17036055
Subject Item
_:vb5924926
rdf:type
n3:Context
rdf:value
It has previously been demonstrated that the Mus81–Eme1 complex is involved in converting ICLs into DSBs (37) independently to the ERCC1–XPF endonuclease activity (>>16<<,20). Here, we examined the DSBs induced by mitomycin C in HR-defective irs1SF [XRCC3 mutated (38)] and ERCC1 mutated UV4DR7 cells and compared with the UV4DR7 cells complemented to a vector expressing wild-type ERCC1, ERCC1.17 (22). We
n3:mentions
n2:11027268
Subject Item
_:vb5924927
rdf:type
n3:Context
rdf:value
It has previously been demonstrated that the Mus81–Eme1 complex is involved in converting ICLs into DSBs (37) independently to the ERCC1–XPF endonuclease activity (16,>>20<<). Here, we examined the DSBs induced by mitomycin C in HR-defective irs1SF [XRCC3 mutated (38)] and ERCC1 mutated UV4DR7 cells and compared with the UV4DR7 cells complemented to a vector expressing wild-type ERCC1, ERCC1.17 (22). We found
n3:mentions
n2:15199134
Subject Item
_:vb5924928
rdf:type
n3:Context
rdf:value
Here, we examined the DSBs induced by mitomycin C in HR-defective irs1SF [XRCC3 mutated (>>38<<)] and ERCC1 mutated UV4DR7 cells and compared with the UV4DR7 cells complemented to a vector expressing wild-type ERCC1, ERCC1.17 (22).
n3:mentions
n2:7603995
Subject Item
_:vb5924929
rdf:type
n3:Context
rdf:value
Here, we examined the DSBs induced by mitomycin C in HR-defective irs1SF [XRCC3 mutated (38)] and ERCC1 mutated UV4DR7 cells and compared with the UV4DR7 cells complemented to a vector expressing wild-type ERCC1, ERCC1.17 (>>22<<). We found a dose-dependent increase in DSBs following a 4-h treatment with mitomycin C (Figure 3) and that DSBs were induced in ERCC1 mutated cells with equal efficiency, as compared to ERCC1 complemented cells, which was in agreement
n3:mentions
n2:17962301
Subject Item
_:vb5924930
rdf:type
n3:Context
rdf:value
increase in DSBs following a 4-h treatment with mitomycin C (Figure 3) and that DSBs were induced in ERCC1 mutated cells with equal efficiency, as compared to ERCC1 complemented cells, which was in agreement with previous observations (>>16<<,20). We also found that DSBs were produced equally efficiently in HR-defective irs1SF cells.
n3:mentions
n2:11027268
Subject Item
_:vb5924931
rdf:type
n3:Context
rdf:value
in DSBs following a 4-h treatment with mitomycin C (Figure 3) and that DSBs were induced in ERCC1 mutated cells with equal efficiency, as compared to ERCC1 complemented cells, which was in agreement with previous observations (16,>>20<<). We also found that DSBs were produced equally efficiently in HR-defective irs1SF cells.
n3:mentions
n2:15199134
Subject Item
_:vb5924932
rdf:type
n3:Context
rdf:value
It has previously been shown that DSBs are only formed by cross-linkers in S-phase cells (>>16<<,20), suggesting that they occur at crosslink-stalled replication forks. Here, we wanted to test if DSB formation also requires an active polymerase elongating the replication fork.
n3:mentions
n2:11027268
Subject Item
_:vb5924933
rdf:type
n3:Context
rdf:value
It has previously been shown that DSBs are only formed by cross-linkers in S-phase cells (16,>>20<<), suggesting that they occur at crosslink-stalled replication forks. Here, we wanted to test if DSB formation also requires an active polymerase elongating the replication fork.
n3:mentions
n2:15199134
Subject Item
_:vb5924934
rdf:type
n3:Context
rdf:value
To test this we inhibited replication elongation with the replication inhibitor aphidicolin, which specifically inhibits DNA polymerase α (>>39<<). Figure 3.
n3:mentions
n2:692726
Subject Item
_:vb5924935
rdf:type
n3:Context
rdf:value
To test this, we used a method that uses the single-stranded DNA ends at a replication fork as starting points for DNA unwinding in alkaline solution (>>40<<). The cells were pulse-labelled for 30 min with 3H-thymidine and the speed of replication fork elongation is monitored as the time required for the labelled DNA to be progressed into the double-stranded DNA fraction following alkaline
n3:mentions
n2:15324747
Subject Item
_:vb5924936
rdf:type
n3:Context
rdf:value
(A) Replication elongation can be measured as the time it takes to prevent release of 3H-thymidine-labelled DNA onto the ssDNA fraction (>>37<<). (B) Time-course of replication fork progression in AA8 cells after a 15-min MMC treatment (100 µM). (C) Dose-dependent replication elongation inhibition in AA8 hamster cells 2 h following MMC treatments. The means and standard deviation
n3:mentions
n2:17036055
Subject Item
_:vb5924937
rdf:type
n3:Context
rdf:value
The first model would be that NER incises the ICL in an attempt to repair the lesion (>>19<<), but fails as a consequence of the opposing strands being covalently cross-linked.
n3:mentions
n2:10882712
Subject Item
_:vb5924938
rdf:type
n3:Context
rdf:value
The incised ICL lesion, which includes a DNA SSB (>>19<<), could then be encountered by an oncoming replication fork and convert the SSB into a one-sided DSB, similarly to the conversion of a camptothecin stabilized topoisomerase I complex into a one-ended DSB (41,42).
n3:mentions
n2:10882712
Subject Item
_:vb5924939
rdf:type
n3:Context
rdf:value
which includes a DNA SSB (19), could then be encountered by an oncoming replication fork and convert the SSB into a one-sided DSB, similarly to the conversion of a camptothecin stabilized topoisomerase I complex into a one-ended DSB (>>41<<,42). This model is supported by the results showing replication elongation is required for DSB formation (Figure 4).
n3:mentions
n2:11292338
Subject Item
_:vb5924940
rdf:type
n3:Context
rdf:value
which includes a DNA SSB (19), could then be encountered by an oncoming replication fork and convert the SSB into a one-sided DSB, similarly to the conversion of a camptothecin stabilized topoisomerase I complex into a one-ended DSB (41,>>42<<). This model is supported by the results showing replication elongation is required for DSB formation (Figure 4).
n3:mentions
n2:10805740
Subject Item
_:vb5924941
rdf:type
n3:Context
rdf:value
An alternative nonexclusive model is that the replication fork is stalled at the cross-link lesion and awaits endonucleases to convert the stalled fork into a DSB, as suggested by the requirement for Mus81 for mitomycin C-induced DSBs (>>37<<), which is mediated by Snm1B (43). In an attempt to distinguish between these two distinct models of ICL repair, we quantified global genome NER-associated incisions following mitomycin C treatment.
n3:mentions
n2:17036055
Subject Item
_:vb5924942
rdf:type
n3:Context
rdf:value
is that the replication fork is stalled at the cross-link lesion and awaits endonucleases to convert the stalled fork into a DSB, as suggested by the requirement for Mus81 for mitomycin C-induced DSBs (37), which is mediated by Snm1B (>>43<<). In an attempt to distinguish between these two distinct models of ICL repair, we quantified global genome NER-associated incisions following mitomycin C treatment.
n3:mentions
n2:18469862
Subject Item
_:vb5924943
rdf:type
n3:Context
rdf:value
We added hydroxyurea and cytosine arabinocide to cells to prevent NER polymerization and ligation of any incised SSBs after mitomycin C exposures, and then used the alkaline DNA unwinding assay, which detects SSBs (>>27<<). As expected using this method we found robust accumulation of SSBs in wild-type AA8 cells following exposure to UVC treatments (Figure 6A), as these cells are proficient in global genome repair of UV lesions. In contrast, ERCC1
n3:mentions
n2:15537835
Subject Item
_:vb5924944
rdf:type
n3:Context
rdf:value
These results are in contrast to data showing that ICL are excised by NER, in transcribed sequences on extrachromosomal plasmids (>>6<<). It is important to point out that we are only measuring incisions globally and are unable to detect few incisions in transcribed DNA. The ADU technique used here utilises the separation of the strands in order to detect the incised SSB.
n3:mentions
n2:12509472
Subject Item
_:vb5924945
rdf:type
n3:Context
rdf:value
The efficiency of nucleotide excision repair (NER) incisions can be measured by the amount of SSBs incised following DNA damage, as measured by alkaline DNA unwinding technique (>>27<<). The NER polymerization step is inhibited using hydroxyurea (2 mM) and cytosine arabinocide (20 µM). Incision of SSB by NER in (A) wild-type AA8 or (B) ERCC1-defective UV4 cells following exposure to increasing doses of UVC. Incision of
n3:mentions
n2:15537835
Subject Item
_:vb5924946
rdf:type
n3:Context
rdf:value
Since ERCC1-defective cells are more sensitive to ICLs than cells mutated in other NER genes, it is suggested that the role of ERCC1–XPF in ICL is separate from its role in NER (>>16<<,25). Our data, showing that mitomycin C-induced DNA lesions are poor substrates for NER, support this notion.
n3:mentions
n2:11027268
Subject Item
_:vb5924947
rdf:type
n3:Context
rdf:value
Since ERCC1-defective cells are more sensitive to ICLs than cells mutated in other NER genes, it is suggested that the role of ERCC1–XPF in ICL is separate from its role in NER (16,>>25<<). Our data, showing that mitomycin C-induced DNA lesions are poor substrates for NER, support this notion.
n3:mentions
n2:18192062
Subject Item
_:vb5924948
rdf:type
n3:Context
rdf:value
ERCC1–XPF does have a role in single-strand annealing and gene conversion during HR (>>22<<), as well as a role in micro-homology-mediated end joining of DSBs (44), two functions for this protein complex that may be particularly important in the process of ICL repair.
n3:mentions
n2:17962301
Subject Item
_:vb5924949
rdf:type
n3:Context
rdf:value
ERCC1–XPF does have a role in single-strand annealing and gene conversion during HR (22), as well as a role in micro-homology-mediated end joining of DSBs (>>44<<), two functions for this protein complex that may be particularly important in the process of ICL repair.
n3:mentions
n2:18541667
Subject Item
_:vb5924950
rdf:type
n3:Context
rdf:value
The RAD51 protein catalyzes the strand invasion process during HR and is relocated into nuclear foci following DNA damage (>>45<<). It is well established that proteins involved in HR (e.g. RAD51 paralogs and BRCA2) are required for RAD51 foci formation (46,47). Here, we find that RAD51 foci form in response to both cisplatin and mitomycin C (Figure 7), in agreement
n3:mentions
n2:7892263
Subject Item
_:vb5924951
rdf:type
n3:Context
rdf:value
It is well established that proteins involved in HR (e.g. RAD51 paralogs and BRCA2) are required for RAD51 foci formation (>>46<<,47). Here, we find that RAD51 foci form in response to both cisplatin and mitomycin C (Figure 7), in agreement with that HR is important in repair of cross-link lesions (48,49). Furthermore, we find that ERCC1-defective UV4DR.7 cells form
n3:mentions
n2:11283264
Subject Item
_:vb5924952
rdf:type
n3:Context
rdf:value
It is well established that proteins involved in HR (e.g. RAD51 paralogs and BRCA2) are required for RAD51 foci formation (46,>>47<<). Here, we find that RAD51 foci form in response to both cisplatin and mitomycin C (Figure 7), in agreement with that HR is important in repair of cross-link lesions (48,49). Furthermore, we find that ERCC1-defective UV4DR.7 cells form
n3:mentions
n2:10446958
Subject Item
_:vb5924953
rdf:type
n3:Context
rdf:value
Here, we find that RAD51 foci form in response to both cisplatin and mitomycin C (Figure 7), in agreement with that HR is important in repair of cross-link lesions (>>48<<,49). Furthermore, we find that ERCC1-defective UV4DR.7 cells form RAD51 foci equally well as the same cells complemented with wild-type ERCC1 (Figure 7B), suggesting that ERCC1 is not critical for RAD51 loading at DSBs and initiation of
n3:mentions
n2:12915460
Subject Item
_:vb5924954
rdf:type
n3:Context
rdf:value
Here, we find that RAD51 foci form in response to both cisplatin and mitomycin C (Figure 7), in agreement with that HR is important in repair of cross-link lesions (48,>>49<<). Furthermore, we find that ERCC1-defective UV4DR.7 cells form RAD51 foci equally well as the same cells complemented with wild-type ERCC1 (Figure 7B), suggesting that ERCC1 is not critical for RAD51 loading at DSBs and initiation of HR.
n3:mentions
n2:16756962
Subject Item
_:vb5924955
rdf:type
n3:Context
rdf:value
7 cell line that also carry the DRneo recombination reporter (>>22<<). ERCC1-defective UV4DR.
n3:mentions
n2:17962301
Subject Item
_:vb5924956
rdf:type
n3:Context
rdf:value
7 cells are only partially defective in an I-SceI-induced DSB, which is explained by ERCC1 being involved in completion of a subset of recombination events when 3′ ssDNA flaps are formed (>>22<<). Here, we investigated the recombination frequency induced by mitomycin C and found that HR is not induced in ERCC1-defective UV4DR.7 or in the plasmid control transfected PEF7 clone (Figure 8). In contrast, equally toxic doses of
n3:mentions
n2:17962301
Subject Item
_:vb5924957
rdf:type
n3:Context
rdf:value
These results are in agreement with Zhang and co-workers (>>50<<), who reported that ICL-induced recombination is impaired in ERCC1 defective cells, using an extra-chromosomal plasmid-based assay.
n3:mentions
n2:17669695
Subject Item
_:vb5924958
rdf:type
n8:Section
dc:title
discussion
n8:contains
_:vb5924959 _:vb5924984 _:vb5924985 _:vb5924986 _:vb5924980 _:vb5924981 _:vb5924982 _:vb5924983 _:vb5924976 _:vb5924977 _:vb5924978 _:vb5924979 _:vb5924972 _:vb5924973 _:vb5924974 _:vb5924975 _:vb5924968 _:vb5924969 _:vb5924970 _:vb5924971 _:vb5924964 _:vb5924965 _:vb5924966 _:vb5924967 _:vb5924960 _:vb5924961 _:vb5924962 _:vb5924963
Subject Item
_:vb5924959
rdf:type
n3:Context
rdf:value
For instance, cisplatin is highly efficient in treatment of testicular cancer, while other ICL agents are less effective (>>51<<). The reason for the difference in anti-cancer activity most likely depends on the particular types of DNA lesions formed. For instance, cisplatin does not form detectible DSBs, in contrast to mitomycin C (7,16). In this study we show
n3:mentions
n2:6209762
Subject Item
_:vb5924960
rdf:type
n3:Context
rdf:value
For instance, cisplatin does not form detectible DSBs, in contrast to mitomycin C (>>7<<,16). In this study we show that ERCC1-defective cells are more sensitive to mitomycin C and cisplatin than HR defective cells and that the opposite is true following treatments with melphalan (Figure 1). This observation underscores the
n3:mentions
n2:12202770
Subject Item
_:vb5924961
rdf:type
n3:Context
rdf:value
For instance, cisplatin does not form detectible DSBs, in contrast to mitomycin C (7,>>16<<). In this study we show that ERCC1-defective cells are more sensitive to mitomycin C and cisplatin than HR defective cells and that the opposite is true following treatments with melphalan (Figure 1). This observation underscores the
n3:mentions
n2:11027268
Subject Item
_:vb5924962
rdf:type
n3:Context
rdf:value
Indeed, ERCC1 has been shown to have a role in recombination-independent ICL repair, supporting this notion (>>6<<).
n3:mentions
n2:12509472
Subject Item
_:vb5924963
rdf:type
n3:Context
rdf:value
Previous studies have established that the formation of DSBs by ICL agents is linked with replication during the S-phase of the cell cycle (>>3<<,16,20,35,52). Here, we confirm these results and show that mitomycin C-induced DSBs are prevented by arrest of replication elongation.
n3:mentions
n2:11516927
Subject Item
_:vb5924964
rdf:type
n3:Context
rdf:value
Previous studies have established that the formation of DSBs by ICL agents is linked with replication during the S-phase of the cell cycle (3,>>16<<,20,35,52). Here, we confirm these results and show that mitomycin C-induced DSBs are prevented by arrest of replication elongation.
n3:mentions
n2:11027268
Subject Item
_:vb5924965
rdf:type
n3:Context
rdf:value
Previous studies have established that the formation of DSBs by ICL agents is linked with replication during the S-phase of the cell cycle (3,16,>>20<<,35,52). Here, we confirm these results and show that mitomycin C-induced DSBs are prevented by arrest of replication elongation.
n3:mentions
n2:15199134
Subject Item
_:vb5924966
rdf:type
n3:Context
rdf:value
Previous studies have established that the formation of DSBs by ICL agents is linked with replication during the S-phase of the cell cycle (3,16,20,>>35<<,52). Here, we confirm these results and show that mitomycin C-induced DSBs are prevented by arrest of replication elongation.
n3:mentions
n2:15944449
Subject Item
_:vb5924967
rdf:type
n3:Context
rdf:value
Previous studies have established that the formation of DSBs by ICL agents is linked with replication during the S-phase of the cell cycle (3,16,20,35,>>52<<). Here, we confirm these results and show that mitomycin C-induced DSBs are prevented by arrest of replication elongation.
n3:mentions
n2:11027296
Subject Item
_:vb5924968
rdf:type
n3:Context
rdf:value
It has been shown that NER is able to incise at cross-links in vitro (>>19<<) and it has then been proposed that the associated SSBs may collapse replication forks into a one-sided DSB.
n3:mentions
n2:10882712
Subject Item
_:vb5924969
rdf:type
n3:Context
rdf:value
Instead, our data support a model where the replication fork is first stalled by the ICL lesion, and then processed into a DSB, which is supported by Mus81 being required for mitomycin C-induced DSBs (>>37<<).
n3:mentions
n2:17036055
Subject Item
_:vb5924970
rdf:type
n3:Context
rdf:value
Interestingly, we find that the ICL-inhibition of replication elongation is not as efficient as equitoxic doses of UV damage (>>27<<). Thus, decreased BrdU incorporation in ICL-treated cells is explained primarily by loss of replication initiation rather than efficient inhibition of replication elongation.
n3:mentions
n2:15537835
Subject Item
_:vb5924971
rdf:type
n3:Context
rdf:value
This recombination-independent ICL repair requires CSA and CSB proteins that are exclusively involved in transcription-coupled repair (TCR) (>>6<<). Thus, we conclude that ICL lesions can be detected and incised in a transcription-dependent manner, which would be confined to transcribed DNA. This is also supported by the insensitivity of GGR defective XPC cells to the toxic effects
n3:mentions
n2:12509472
Subject Item
_:vb5924972
rdf:type
n3:Context
rdf:value
This is also supported by the insensitivity of GGR defective XPC cells to the toxic effects of cisplatin (>>53<<).
n3:mentions
n2:12208738
Subject Item
_:vb5924973
rdf:type
n3:Context
rdf:value
The ERCC1–XPF complex is implicated in HR (21–>>24<<) and it has been suggested that this is the role for ERCC1–XPF in ICL repair (25,35,50).
n3:mentions
n2:11000269 n2:11032822 n2:11707424 n2:17962301
Subject Item
_:vb5924974
rdf:type
n3:Context
rdf:value
The ERCC1–XPF complex is implicated in HR (21–24) and it has been suggested that this is the role for ERCC1–XPF in ICL repair (>>25<<,35,50). Here, we report that ERCC1-defective cells are proficient in forming RAD51 foci after cisplatin or mitomycin C treatments.
n3:mentions
n2:18192062
Subject Item
_:vb5924975
rdf:type
n3:Context
rdf:value
The ERCC1–XPF complex is implicated in HR (21–24) and it has been suggested that this is the role for ERCC1–XPF in ICL repair (25,>>35<<,50). Here, we report that ERCC1-defective cells are proficient in forming RAD51 foci after cisplatin or mitomycin C treatments.
n3:mentions
n2:15944449
Subject Item
_:vb5924976
rdf:type
n3:Context
rdf:value
The ERCC1–XPF complex is implicated in HR (21–24) and it has been suggested that this is the role for ERCC1–XPF in ICL repair (25,35,>>50<<). Here, we report that ERCC1-defective cells are proficient in forming RAD51 foci after cisplatin or mitomycin C treatments.
n3:mentions
n2:17669695
Subject Item
_:vb5924977
rdf:type
n3:Context
rdf:value
initiated normally in ERCC1-defective cells, the ERCC1–XPF being likely to have a role in HR in a step subsequent to the activities of the HR proteins RAD51D, XRCC3 or BRCA2, as those mutant cells are deficient in RAD51 foci formation (>>46<<,47). Using a recombination reporter, we also found that ERCC1 mutant cells are impaired in mitomycin C-induced HR, and that the defect can be reverted by introduction of a functional ERCC1 gene expressed from a vector.
n3:mentions
n2:11283264
Subject Item
_:vb5924978
rdf:type
n3:Context
rdf:value
normally in ERCC1-defective cells, the ERCC1–XPF being likely to have a role in HR in a step subsequent to the activities of the HR proteins RAD51D, XRCC3 or BRCA2, as those mutant cells are deficient in RAD51 foci formation (46,>>47<<). Using a recombination reporter, we also found that ERCC1 mutant cells are impaired in mitomycin C-induced HR, and that the defect can be reverted by introduction of a functional ERCC1 gene expressed from a vector.
n3:mentions
n2:10446958
Subject Item
_:vb5924979
rdf:type
n3:Context
rdf:value
These results are in agreement with previous data showing that ERCC1 is required for ICL-induced recombination on an extra-chromosomal plasmid (>>50<<). The complete deficiency of ERCC1 mutant cells to induce HR after mitomycin C treatment is not a simple reflection of ERCC1–XPF being required for all types of HR events, as a two-ended I-SceI-induced DSB still triggers recombination
n3:mentions
n2:17669695
Subject Item
_:vb5924980
rdf:type
n3:Context
rdf:value
7 cells (>>22<<). Thus, it is likely that the ERCC1–XPF complex is specifically involved in ICL-induced HR, likely involved in resolving late-stage recombination products.
n3:mentions
n2:17962301
Subject Item
_:vb5924981
rdf:type
n3:Context
rdf:value
The RNA polymerase will either backtrack or be degraded during subsequent repair, which proceed through TLS, using Polη, Rev1 or Rev3 (>>61<<). NER factors will be attracted for second incision that will remove the ICL to allow resumption of transcription.
n3:mentions
n2:16571727
Subject Item
_:vb5924982
rdf:type
n3:Context
rdf:value
In replication-initiated ICL repair, replication forks will stall at the ICL lesion and the initial DSB is catalysed by Mus81 (>>37<<) and not by replication run off.
n3:mentions
n2:17036055
Subject Item
_:vb5924983
rdf:type
n3:Context
rdf:value
The released one-sided DSB is likely resected by the Mre11-RAD50-Nbs1 complex (>>54<<) and subsequently coated with the RAD51 protein.
n3:mentions
n2:18854157
Subject Item
_:vb5924984
rdf:type
n3:Context
rdf:value
An opposing second replication fork likely arrives at the crosslink (>>55<<), and the ERCC1–XPF complex could unhook this replication fork to allow TLS, possibly with Rev1 or Polζ (56).
n3:mentions
n2:18805090
Subject Item
_:vb5924985
rdf:type
n3:Context
rdf:value
An opposing second replication fork likely arrives at the crosslink (55), and the ERCC1–XPF complex could unhook this replication fork to allow TLS, possibly with Rev1 or Polζ (>>56<<). The ligated DNA molecule would be invaded by RAD51 to initiate synthesis-dependent strand annealing (57) and the final lesion removed by NER. In transcription-initiated ICL repair, ICL lesions are recognised by the RNA polymerase, as
n3:mentions
n2:17363342
Subject Item
_:vb5924986
rdf:type
n3:Context
rdf:value
The ligated DNA molecule would be invaded by RAD51 to initiate synthesis-dependent strand annealing (>>57<<) and the final lesion removed by NER.
n3:mentions
n2:17363343
Subject Item
_:vb412614056
rdf:type
n3:RelevantBibliographicResource
n3:RelevantScore
3
n3:hasRelevantPaperId
n2:11027268
Subject Item
_:vb412614057
rdf:type
n3:RelevantBibliographicResource
n3:RelevantScore
3
n3:hasRelevantPaperId
n2:11027296
Subject Item
_:vb412614058
rdf:type
n3:RelevantBibliographicResource
n3:RelevantScore
3
n3:hasRelevantPaperId
n2:21423196
Subject Item
_:vb412614059
rdf:type
n3:RelevantBibliographicResource
n3:RelevantScore
3
n3:hasRelevantPaperId
n2:18805090
Subject Item
_:vb412614060
rdf:type
n3:RelevantBibliographicResource
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