Flipping of Alkylated DNA Damage Bridges Base and Nucleotide Excision Repair

Overview

Journal Nature

Specialty Science

Date 2009 Jun 12

PMID 19516334

Citations 79

Authors

Julie L Tubbs

Vitaly Latypov

Sreenivas Kanugula

Amna Butt

Manana Melikishvili

Rolf Kraehenbuehl

Oliver Fleck

Andrew Marriott

Amanda J Watson

Barbara Verbeek

Gail McGown

Mary Thorncroft

Mauro F Santibanez-Koref

Christopher Millington

Andrew S Arvai

Matthew D Kroeger

Lisa A Peterson

David M Williams

Michael G Fried

Geoffrey P Margison

Anthony E Pegg

John A Tainer

Affiliations

Soon will be listed here.

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.

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References

Scharer O, Campbell A . Wedging out DNA damage. Nat Struct Mol Biol. 2009; 16(2):102-4. PMC: 2745198. DOI: 10.1038/nsmb0209-102. View

Elkins J, Podar M, Graham D, Makarova K, Wolf Y, Randau L . A korarchaeal genome reveals insights into the evolution of the Archaea. Proc Natl Acad Sci U S A. 2008; 105(23):8102-7. PMC: 2430366. DOI: 10.1073/pnas.0801980105. View

Chen C, Korobkova E, Chen H, Zhu J, Jian X, Tao S . A proteome chip approach reveals new DNA damage recognition activities in Escherichia coli. Nat Methods. 2007; 5(1):69-74. PMC: 2576280. DOI: 10.1038/nmeth1148. View

Sedgwick B . Repairing DNA-methylation damage. Nat Rev Mol Cell Biol. 2004; 5(2):148-57. DOI: 10.1038/nrm1312. View

Margison G, Santibanez-Koref M . O6-alkylguanine-DNA alkyltransferase: role in carcinogenesis and chemotherapy. Bioessays. 2002; 24(3):255-66. DOI: 10.1002/bies.10063. View

HICKMAN M, Samson L . Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents. Proc Natl Acad Sci U S A. 1999; 96(19):10764-9. PMC: 17957. DOI: 10.1073/pnas.96.19.10764. View

Mijal R, Thomson N, Fleischer N, Pauly G, Moschel R, Kanugula S . The repair of the tobacco specific nitrosamine derived adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by O6-alkylguanine-DNA alkyltransferase variants. Chem Res Toxicol. 2004; 17(3):424-34. DOI: 10.1021/tx0342417. View

Chapados B, Hosfield D, Han S, Qiu J, Yelent B, Shen B . Structural basis for FEN-1 substrate specificity and PCNA-mediated activation in DNA replication and repair. Cell. 2004; 116(1):39-50. DOI: 10.1016/s0092-8674(03)01036-5. View

Klungland A, Lindahl T . Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO J. 1997; 16(11):3341-8. PMC: 1169950. DOI: 10.1093/emboj/16.11.3341. View

10.

Mazon G, Philippin G, Cadet J, Gasparutto D, Fuchs R . The alkyltransferase-like ybaZ gene product enhances nucleotide excision repair of O(6)-alkylguanine adducts in E. coli. DNA Repair (Amst). 2009; 8(6):697-703. DOI: 10.1016/j.dnarep.2009.01.022. View

11.

Kanugula S, Pauly G, Moschel R, Pegg A . A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O6-alkylguanine-DNA alkyltransferase and endonuclease V activities. Proc Natl Acad Sci U S A. 2005; 102(10):3617-22. PMC: 553313. DOI: 10.1073/pnas.0408719102. View

12.

Hu J, Ma A, Dinner A . A two-step nucleotide-flipping mechanism enables kinetic discrimination of DNA lesions by AGT. Proc Natl Acad Sci U S A. 2008; 105(12):4615-20. PMC: 2290773. DOI: 10.1073/pnas.0708058105. View

13.

Daniels D, Mol C, Arvai A, Kanugula S, Pegg A, Tainer J . Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. EMBO J. 2000; 19(7):1719-30. PMC: 310240. DOI: 10.1093/emboj/19.7.1719. View

14.

Putnam N, Srivastava M, Hellsten U, Dirks B, Chapman J, Salamov A . Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science. 2007; 317(5834):86-94. DOI: 10.1126/science.1139158. View

15.

Duguid E, Rice P, He C . The structure of the human AGT protein bound to DNA and its implications for damage detection. J Mol Biol. 2005; 350(4):657-66. DOI: 10.1016/j.jmb.2005.05.028. View

16.

Pearson S, Ferguson J, Santibanez-Koref M, Margison G . Inhibition of O6-methylguanine-DNA methyltransferase by an alkyltransferase-like protein from Escherichia coli. Nucleic Acids Res. 2005; 33(12):3837-44. PMC: 1175458. DOI: 10.1093/nar/gki696. View

17.

Parikh S, Walcher G, Jones G, Slupphaug G, Krokan H, Blackburn G . Uracil-DNA glycosylase-DNA substrate and product structures: conformational strain promotes catalytic efficiency by coupled stereoelectronic effects. Proc Natl Acad Sci U S A. 2000; 97(10):5083-8. PMC: 25785. DOI: 10.1073/pnas.97.10.5083. View

18.

Mol C, Izumi T, Mitra S, Tainer J . DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected]. Nature. 2000; 403(6768):451-6. DOI: 10.1038/35000249. View

19.

Loechler E, Green C, Essigmann J . In vivo mutagenesis by O6-methylguanine built into a unique site in a viral genome. Proc Natl Acad Sci U S A. 1984; 81(20):6271-5. PMC: 391905. DOI: 10.1073/pnas.81.20.6271. View

20.

Pegg A, Dolan M, Moschel R . Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol. 1995; 51:167-223. DOI: 10.1016/s0079-6603(08)60879-x. View