Structural insight into dynamic bypass of the major cisplatin‐DNA adduct by Y‐family polymerase Dpo4
Identifieur interne : 002683 ( Main/Exploration ); précédent : 002682; suivant : 002684Structural insight into dynamic bypass of the major cisplatin‐DNA adduct by Y‐family polymerase Dpo4
Auteurs : Jimson Hy Wong [Canada] ; Jessica A. Brown [États-Unis] ; Zucai Suo [États-Unis] ; Paul Blum [États-Unis] ; Takehiko Nohmi [Japon] ; Hong Ling [Canada]Source :
- The EMBO Journal [ 0261-4189 ] ; 2010-06-16.
English descriptors
- Teeft :
- Acta crystallogr, Active site, Adduct, Alternate conformations, Anticancer, Anticancer drug cisplatin, Assay, Base pair, Base pairs, Biochemistry, Biol, Biol chem, Biol crystallogr, Biology organization, Chaney, Cisplatin, Cisplatin resistance, Conformation, Conformational change, Conformational changes, Crystal structure, Dctp, Dctp insertion, Delity, Depressed conformation, Dntp, Dpo4, Electron density, Embo, Embo journal, Extension step, Helical, Helical structure, Helix, Hyperthermophilic archaeon sulfolobus solfataricus, Incoming dctp, Incoming nucleotide, Incorporation, Insertion, Insertion stages, Lesion, Ling, Lippard, Major adduct, Major groove, Mutant, Mutation, Nger, Nger domain, Nucleotide, Nucleotide incorporation, Platinum atom, Polymerase, Polymerase beta, Primer, Primer strand, Proc natl acad, Reaction stages, Regular position, Replication, Roll angle, Roll angles, Second insertion, Solfataricus, Straight form, Structural basis, Structural differences, Supplementary data, Supplementary figure, Supplementary table, Takahara, Template, Template strand, Ternary, Ternary complexes, Torsion, Torsion angles, Translesion, Translesion synthesis, Tumour cells, Undamaged, Vaisman, Wong, Woodgate, Ypolz.
Abstract
Y‐family DNA polymerases bypass Pt‐GG, the cisplatin‐DNA double‐base lesion, contributing to the cisplatin resistance in tumour cells. To reveal the mechanism, we determined three structures of the Y‐family DNA polymerase, Dpo4, in complex with Pt‐GG DNA. The crystallographic snapshots show three stages of lesion bypass: the nucleotide insertions opposite the 3′G (first insertion) and 5′G (second insertion) of Pt‐GG, and the primer extension beyond the lesion site. We observed a dynamic process, in which the lesion was converted from an open and angular conformation at the first insertion to a depressed and nearly parallel conformation at the subsequent reaction stages to fit into the active site of Dpo4. The DNA translocation‐coupled conformational change may account for additional inhibition on the second insertion reaction. The structures illustrate that Pt‐GG disturbs the replicating base pair in the active site, which reduces the catalytic efficiency and fidelity. The in vivo relevance of Dpo4‐mediated Pt‐GG bypass was addressed by a dpo‐4 knockout strain of Sulfolobus solfataricus, which exhibits enhanced sensitivity to cisplatin and proteomic alterations consistent with genomic stress.
Url:
DOI: 10.1038/emboj.2010.101
Affiliations:
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Journal</title><title level="j" type="alt">THE EMBO JOURNAL</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><biblScope unit="vol">29</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="2059">2059</biblScope><biblScope unit="page" to="2069">2069</biblScope><biblScope unit="page-count">11</biblScope><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2010-06-16">2010-06-16</date></imprint><idno type="ISSN">0261-4189</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0261-4189</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acta crystallogr</term><term>Active site</term><term>Adduct</term><term>Alternate conformations</term><term>Anticancer</term><term>Anticancer drug cisplatin</term><term>Assay</term><term>Base pair</term><term>Base pairs</term><term>Biochemistry</term><term>Biol</term><term>Biol chem</term><term>Biol crystallogr</term><term>Biology organization</term><term>Chaney</term><term>Cisplatin</term><term>Cisplatin resistance</term><term>Conformation</term><term>Conformational change</term><term>Conformational changes</term><term>Crystal structure</term><term>Dctp</term><term>Dctp insertion</term><term>Delity</term><term>Depressed conformation</term><term>Dntp</term><term>Dpo4</term><term>Electron density</term><term>Embo</term><term>Embo journal</term><term>Extension step</term><term>Helical</term><term>Helical structure</term><term>Helix</term><term>Hyperthermophilic archaeon sulfolobus solfataricus</term><term>Incoming dctp</term><term>Incoming nucleotide</term><term>Incorporation</term><term>Insertion</term><term>Insertion stages</term><term>Lesion</term><term>Ling</term><term>Lippard</term><term>Major adduct</term><term>Major groove</term><term>Mutant</term><term>Mutation</term><term>Nger</term><term>Nger domain</term><term>Nucleotide</term><term>Nucleotide incorporation</term><term>Platinum atom</term><term>Polymerase</term><term>Polymerase beta</term><term>Primer</term><term>Primer strand</term><term>Proc natl acad</term><term>Reaction stages</term><term>Regular position</term><term>Replication</term><term>Roll angle</term><term>Roll angles</term><term>Second insertion</term><term>Solfataricus</term><term>Straight form</term><term>Structural basis</term><term>Structural differences</term><term>Supplementary data</term><term>Supplementary figure</term><term>Supplementary table</term><term>Takahara</term><term>Template</term><term>Template strand</term><term>Ternary</term><term>Ternary complexes</term><term>Torsion</term><term>Torsion angles</term><term>Translesion</term><term>Translesion synthesis</term><term>Tumour cells</term><term>Undamaged</term><term>Vaisman</term><term>Wong</term><term>Woodgate</term><term>Ypolz</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract">Y‐family DNA polymerases bypass Pt‐GG, the cisplatin‐DNA double‐base lesion, contributing to the cisplatin resistance in tumour cells. To reveal the mechanism, we determined three structures of the Y‐family DNA polymerase, Dpo4, in complex with Pt‐GG DNA. The crystallographic snapshots show three stages of lesion bypass: the nucleotide insertions opposite the 3′G (first insertion) and 5′G (second insertion) of Pt‐GG, and the primer extension beyond the lesion site. We observed a dynamic process, in which the lesion was converted from an open and angular conformation at the first insertion to a depressed and nearly parallel conformation at the subsequent reaction stages to fit into the active site of Dpo4. The DNA translocation‐coupled conformational change may account for additional inhibition on the second insertion reaction. The structures illustrate that Pt‐GG disturbs the replicating base pair in the active site, which reduces the catalytic efficiency and fidelity. The in vivo relevance of Dpo4‐mediated Pt‐GG bypass was addressed by a dpo‐4 knockout strain of Sulfolobus solfataricus, which exhibits enhanced sensitivity to cisplatin and proteomic alterations consistent with genomic stress.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Japon</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement></list><tree><country name="Canada"><region name="Angleterre"><name sortKey="Wong, Jimson Hy" sort="Wong, Jimson Hy" uniqKey="Wong J" first="Jimson Hy" last="Wong">Jimson Hy Wong</name></region><name sortKey="Ling, Hong" sort="Ling, Hong" uniqKey="Ling H" first="Hong" last="Ling">Hong Ling</name><name sortKey="Ling, Hong" sort="Ling, Hong" uniqKey="Ling H" first="Hong" last="Ling">Hong Ling</name></country><country name="États-Unis"><noRegion><name sortKey="Brown, Jessica A" sort="Brown, Jessica A" uniqKey="Brown J" first="Jessica A" last="Brown">Jessica A. Brown</name></noRegion><name sortKey="Blum, Paul" sort="Blum, Paul" uniqKey="Blum P" first="Paul" last="Blum">Paul Blum</name><name sortKey="Suo, Zucai" sort="Suo, Zucai" uniqKey="Suo Z" first="Zucai" last="Suo">Zucai Suo</name></country><country name="Japon"><noRegion><name sortKey="Nohmi, Takehiko" sort="Nohmi, Takehiko" uniqKey="Nohmi T" first="Takehiko" last="Nohmi">Takehiko Nohmi</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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