Structural basis of interstrand cross-link repair by -alkylguanine DNA alkyltransferase
DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems. O 6 -Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the O 6 -atom of 2′-deoxyguanosine and the O 4 -atom of thymidine. Human AGT (hAGT) has demonstrated the a...
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| Veröffentlicht in: | Organic & biomolecular chemistry 2017-10, Vol.15 (39), p.8361-837 |
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| creator | Denisov, Alexey Y McManus, Francis P O'Flaherty, Derek K Noronha, Anne M Wilds, Christopher J |
| description | DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems.
O
6
-Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the
O
6
-atom of 2′-deoxyguanosine and the
O
4
-atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two
O
6
-atoms of 2′-deoxyguanosine were tethered by a butylene (
XLGG4
) or heptylene (
XLGG7
) linkage. However, the analogous ICL between the
O
4
-atoms of thymidine was found to evade repair. ICL duplexes connecting the
O
4
-atoms of 2′-deoxyuridine by a butylene (
XLUU4
) or heptylene (
XLUU7
) linkage have been prepared to examine the influence of the C5-methyl group on AGT-mediated repair. Both
XLUU4
and
XLUU7
were refractory to repair by human and
E. coli
(OGT and Ada-C) AGTs with comparably low μM dissociation constants for 2 : 1 or 4 : 1 AGT/DNA stoichiometries. The solution structures of two heptylene linked DNA duplexes (CGAAAYTTTCG)
2
,
XLUU7
(Y = dU) and
XLGG7
(Y = dG), were solved and the global structures were virtually identical with a RMSD of 1.22 Å. The ICL was found to reside in the major groove for both duplexes. The linkage adopts an
E
conformation about the C4-
O
4
bond for
XLUU7
whereas a
Z
conformation about the C6-
O
6
bond was observed for
XLGG7
. This
E versus Z
conformation may partially account for hAGTs discrimination towards the repair of these ICL, supported by the crystal structures of hAGT with various substrates which have been observed to adopt a
Z
conformation. In addition, a higher mobility at the ICL site for
XLUU7
is observed relative to
XLGG7
that may play a role in repair by hAGT. Taken together, these findings provide insights on the AGT-mediated repair of cytotoxic ICL in terms of its processing capability and substrate specificity.
Conformation of the alkylene lesion may play a role in interstrand cross-link repair by
O
6-alkylguanine DNA alkyltransferases. |
| doi_str_mv | 10.1039/c7ob02093g |
| format | Article |
| fullrecord | <record><control><sourceid>rsc</sourceid><recordid>TN_cdi_rsc_primary_c7ob02093g</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>c7ob02093g</sourcerecordid><originalsourceid>FETCH-rsc_primary_c7ob02093g3</originalsourceid><addsrcrecordid>eNqFjrsKwkAQRRdRMD4ae2F-ILp5aEgpPrCyUbAMk7gJa9ZNmEmK_L0ooqXVvZzLgSvEzJMLTwbxMouqVPoyDoqecLwwily5CuL-t_tyKEbMdym9OFqHjrieG2qzpiU0kCJrhioHbRtF3BDaG2RUMbtG2xJI1agJ0g5cNGVnihattgp2pw28wcvgXBGymohBjobV9JNjMT_sL9ujS5wlNekHUpf83gb_9ida4UQs</addsrcrecordid><sourcetype>Publisher</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Structural basis of interstrand cross-link repair by -alkylguanine DNA alkyltransferase</title><source>Royal Society Of Chemistry Journals 2008-</source><source>Alma/SFX Local Collection</source><creator>Denisov, Alexey Y ; McManus, Francis P ; O'Flaherty, Derek K ; Noronha, Anne M ; Wilds, Christopher J</creator><creatorcontrib>Denisov, Alexey Y ; McManus, Francis P ; O'Flaherty, Derek K ; Noronha, Anne M ; Wilds, Christopher J</creatorcontrib><description>DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems.
O
6
-Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the
O
6
-atom of 2′-deoxyguanosine and the
O
4
-atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two
O
6
-atoms of 2′-deoxyguanosine were tethered by a butylene (
XLGG4
) or heptylene (
XLGG7
) linkage. However, the analogous ICL between the
O
4
-atoms of thymidine was found to evade repair. ICL duplexes connecting the
O
4
-atoms of 2′-deoxyuridine by a butylene (
XLUU4
) or heptylene (
XLUU7
) linkage have been prepared to examine the influence of the C5-methyl group on AGT-mediated repair. Both
XLUU4
and
XLUU7
were refractory to repair by human and
E. coli
(OGT and Ada-C) AGTs with comparably low μM dissociation constants for 2 : 1 or 4 : 1 AGT/DNA stoichiometries. The solution structures of two heptylene linked DNA duplexes (CGAAAYTTTCG)
2
,
XLUU7
(Y = dU) and
XLGG7
(Y = dG), were solved and the global structures were virtually identical with a RMSD of 1.22 Å. The ICL was found to reside in the major groove for both duplexes. The linkage adopts an
E
conformation about the C4-
O
4
bond for
XLUU7
whereas a
Z
conformation about the C6-
O
6
bond was observed for
XLGG7
. This
E versus Z
conformation may partially account for hAGTs discrimination towards the repair of these ICL, supported by the crystal structures of hAGT with various substrates which have been observed to adopt a
Z
conformation. In addition, a higher mobility at the ICL site for
XLUU7
is observed relative to
XLGG7
that may play a role in repair by hAGT. Taken together, these findings provide insights on the AGT-mediated repair of cytotoxic ICL in terms of its processing capability and substrate specificity.
Conformation of the alkylene lesion may play a role in interstrand cross-link repair by
O
6-alkylguanine DNA alkyltransferases.</description><identifier>ISSN: 1477-0520</identifier><identifier>EISSN: 1477-0539</identifier><identifier>DOI: 10.1039/c7ob02093g</identifier><ispartof>Organic & biomolecular chemistry, 2017-10, Vol.15 (39), p.8361-837</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Denisov, Alexey Y</creatorcontrib><creatorcontrib>McManus, Francis P</creatorcontrib><creatorcontrib>O'Flaherty, Derek K</creatorcontrib><creatorcontrib>Noronha, Anne M</creatorcontrib><creatorcontrib>Wilds, Christopher J</creatorcontrib><title>Structural basis of interstrand cross-link repair by -alkylguanine DNA alkyltransferase</title><title>Organic & biomolecular chemistry</title><description>DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems.
O
6
-Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the
O
6
-atom of 2′-deoxyguanosine and the
O
4
-atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two
O
6
-atoms of 2′-deoxyguanosine were tethered by a butylene (
XLGG4
) or heptylene (
XLGG7
) linkage. However, the analogous ICL between the
O
4
-atoms of thymidine was found to evade repair. ICL duplexes connecting the
O
4
-atoms of 2′-deoxyuridine by a butylene (
XLUU4
) or heptylene (
XLUU7
) linkage have been prepared to examine the influence of the C5-methyl group on AGT-mediated repair. Both
XLUU4
and
XLUU7
were refractory to repair by human and
E. coli
(OGT and Ada-C) AGTs with comparably low μM dissociation constants for 2 : 1 or 4 : 1 AGT/DNA stoichiometries. The solution structures of two heptylene linked DNA duplexes (CGAAAYTTTCG)
2
,
XLUU7
(Y = dU) and
XLGG7
(Y = dG), were solved and the global structures were virtually identical with a RMSD of 1.22 Å. The ICL was found to reside in the major groove for both duplexes. The linkage adopts an
E
conformation about the C4-
O
4
bond for
XLUU7
whereas a
Z
conformation about the C6-
O
6
bond was observed for
XLGG7
. This
E versus Z
conformation may partially account for hAGTs discrimination towards the repair of these ICL, supported by the crystal structures of hAGT with various substrates which have been observed to adopt a
Z
conformation. In addition, a higher mobility at the ICL site for
XLUU7
is observed relative to
XLGG7
that may play a role in repair by hAGT. Taken together, these findings provide insights on the AGT-mediated repair of cytotoxic ICL in terms of its processing capability and substrate specificity.
Conformation of the alkylene lesion may play a role in interstrand cross-link repair by
O
6-alkylguanine DNA alkyltransferases.</description><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqFjrsKwkAQRRdRMD4ae2F-ILp5aEgpPrCyUbAMk7gJa9ZNmEmK_L0ooqXVvZzLgSvEzJMLTwbxMouqVPoyDoqecLwwily5CuL-t_tyKEbMdym9OFqHjrieG2qzpiU0kCJrhioHbRtF3BDaG2RUMbtG2xJI1agJ0g5cNGVnihattgp2pw28wcvgXBGymohBjobV9JNjMT_sL9ujS5wlNekHUpf83gb_9ida4UQs</recordid><startdate>20171011</startdate><enddate>20171011</enddate><creator>Denisov, Alexey Y</creator><creator>McManus, Francis P</creator><creator>O'Flaherty, Derek K</creator><creator>Noronha, Anne M</creator><creator>Wilds, Christopher J</creator><scope/></search><sort><creationdate>20171011</creationdate><title>Structural basis of interstrand cross-link repair by -alkylguanine DNA alkyltransferase</title><author>Denisov, Alexey Y ; McManus, Francis P ; O'Flaherty, Derek K ; Noronha, Anne M ; Wilds, Christopher J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-rsc_primary_c7ob02093g3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><creationdate>2017</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Denisov, Alexey Y</creatorcontrib><creatorcontrib>McManus, Francis P</creatorcontrib><creatorcontrib>O'Flaherty, Derek K</creatorcontrib><creatorcontrib>Noronha, Anne M</creatorcontrib><creatorcontrib>Wilds, Christopher J</creatorcontrib><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Denisov, Alexey Y</au><au>McManus, Francis P</au><au>O'Flaherty, Derek K</au><au>Noronha, Anne M</au><au>Wilds, Christopher J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis of interstrand cross-link repair by -alkylguanine DNA alkyltransferase</atitle><jtitle>Organic & biomolecular chemistry</jtitle><date>2017-10-11</date><risdate>2017</risdate><volume>15</volume><issue>39</issue><spage>8361</spage><epage>837</epage><pages>8361-837</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><abstract>DNA interstrand cross-links (ICL) are among the most cytotoxic lesions found in biological systems.
O
6
-Alkylguanine DNA alkyltransferases (AGTs) are capable of removing alkylation damage from the
O
6
-atom of 2′-deoxyguanosine and the
O
4
-atom of thymidine. Human AGT (hAGT) has demonstrated the ability to repair an interstrand cross-linked duplex where two
O
6
-atoms of 2′-deoxyguanosine were tethered by a butylene (
XLGG4
) or heptylene (
XLGG7
) linkage. However, the analogous ICL between the
O
4
-atoms of thymidine was found to evade repair. ICL duplexes connecting the
O
4
-atoms of 2′-deoxyuridine by a butylene (
XLUU4
) or heptylene (
XLUU7
) linkage have been prepared to examine the influence of the C5-methyl group on AGT-mediated repair. Both
XLUU4
and
XLUU7
were refractory to repair by human and
E. coli
(OGT and Ada-C) AGTs with comparably low μM dissociation constants for 2 : 1 or 4 : 1 AGT/DNA stoichiometries. The solution structures of two heptylene linked DNA duplexes (CGAAAYTTTCG)
2
,
XLUU7
(Y = dU) and
XLGG7
(Y = dG), were solved and the global structures were virtually identical with a RMSD of 1.22 Å. The ICL was found to reside in the major groove for both duplexes. The linkage adopts an
E
conformation about the C4-
O
4
bond for
XLUU7
whereas a
Z
conformation about the C6-
O
6
bond was observed for
XLGG7
. This
E versus Z
conformation may partially account for hAGTs discrimination towards the repair of these ICL, supported by the crystal structures of hAGT with various substrates which have been observed to adopt a
Z
conformation. In addition, a higher mobility at the ICL site for
XLUU7
is observed relative to
XLGG7
that may play a role in repair by hAGT. Taken together, these findings provide insights on the AGT-mediated repair of cytotoxic ICL in terms of its processing capability and substrate specificity.
Conformation of the alkylene lesion may play a role in interstrand cross-link repair by
O
6-alkylguanine DNA alkyltransferases.</abstract><doi>10.1039/c7ob02093g</doi><tpages>1</tpages></addata></record> |
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| source | Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| title | Structural basis of interstrand cross-link repair by -alkylguanine DNA alkyltransferase |
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