Flipping of alkylated DNA damage bridges base and nucleotide excision repair.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85244
Title:
Flipping of alkylated DNA damage bridges base and nucleotide excision repair.
Authors:
Tubbs, Julie L; Latypov, Vitaly F; Kanugula, Sreenivas; Butt, Amna; Melikishvili, Manana; Kraehenbuehl, Rolf; Fleck, Oliver; Marriott, Andrew S; Watson, Amanda J; Verbeek, Barbara; McGown, Gail; Thorncroft, Mary R; Santibanez-Koref, Mauro F; Millington, Christopher; Arvai, Andrew S; Kroeger, Matthew D; Peterson, Lisa A; Williams, David M; Fried, Mike; Margison, Geoffrey P; Pegg, Anthony E; Tainer, John A
Abstract:
Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.
Affiliation:
Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Citation:
Flipping of alkylated DNA damage bridges base and nucleotide excision repair. 2009, 459 (7248):808-13 Nature
Journal:
Nature
Issue Date:
11-Jun-2009
URI:
http://hdl.handle.net/10541/85244
DOI:
10.1038/nature08076
PubMed ID:
19516334
Type:
Article
Language:
en
ISSN:
1476-4687
Appears in Collections:
All Paterson Institute for Cancer Research; Carcinogenesis Group; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorTubbs, Julie Len
dc.contributor.authorLatypov, Vitaly Fen
dc.contributor.authorKanugula, Sreenivasen
dc.contributor.authorButt, Amnaen
dc.contributor.authorMelikishvili, Mananaen
dc.contributor.authorKraehenbuehl, Rolfen
dc.contributor.authorFleck, Oliveren
dc.contributor.authorMarriott, Andrew Sen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorVerbeek, Barbaraen
dc.contributor.authorMcGown, Gailen
dc.contributor.authorThorncroft, Mary Ren
dc.contributor.authorSantibanez-Koref, Mauro Fen
dc.contributor.authorMillington, Christopheren
dc.contributor.authorArvai, Andrew Sen
dc.contributor.authorKroeger, Matthew Den
dc.contributor.authorPeterson, Lisa Aen
dc.contributor.authorWilliams, David Men
dc.contributor.authorFried, Mikeen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorPegg, Anthony Een
dc.contributor.authorTainer, John Aen
dc.date.accessioned2009-11-03T12:43:20Z-
dc.date.available2009-11-03T12:43:20Z-
dc.date.issued2009-06-11-
dc.identifier.citationFlipping of alkylated DNA damage bridges base and nucleotide excision repair. 2009, 459 (7248):808-13 Natureen
dc.identifier.issn1476-4687-
dc.identifier.pmid19516334-
dc.identifier.doi10.1038/nature08076-
dc.identifier.urihttp://hdl.handle.net/10541/85244-
dc.description.abstractAlkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.en
dc.language.isoenen
dc.subject.meshAlkyl and Aryl Transferases-
dc.subject.meshAlkylation-
dc.subject.meshBinding Sites-
dc.subject.meshCrystallography, X-Ray-
dc.subject.meshDNA-
dc.subject.meshDNA Damage-
dc.subject.meshDNA Repair-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshModels, Molecular-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Conformation-
dc.titleFlipping of alkylated DNA damage bridges base and nucleotide excision repair.en
dc.typeArticleen
dc.contributor.departmentSkaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.en
dc.identifier.journalNatureen

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.