Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools

Chemical Research in Toxicology
Anthony E Pegg

Abstract

O(6)-Alkylguanine-DNA alkyltransferase (AGT) is a widely distributed, unique DNA repair protein that acts as a single agent to directly remove alkyl groups located on the O(6)-position of guanine from DNA restoring the DNA in one step. The protein acts only once, and its alkylated form is degraded rapidly. It is a major factor in counteracting the mutagenic, carcinogenic, and cytotoxic effects of agents that form such adducts including N-nitroso-compounds and a number of cancer chemotherapeutics. This review describes the structure, function, and mechanism of action of AGTs and of a family of related alkyltransferase-like proteins, which do not act alone to repair O(6)-alkylguanines in DNA but link repair to other pathways. The paradoxical ability of AGTs to stimulate the DNA-damaging ability of dihaloalkanes and other bis-electrophiles via the formation of AGT-DNA cross-links is also described. Other important properties of AGTs include the ability to provide resistance to cancer therapeutic alkylating agents, and the availability of AGT inhibitors such as O(6)-benzylguanine that might overcome this resistance is discussed. Finally, the properties of fusion proteins in which AGT sequences are linked to other proteins are outli...Continue Reading

References

May 19, 1977·Nature·Leona D Samson, J Cairns
Sep 14, 1978·Biochemical and Biophysical Research Communications·Anthony E Pegg
Apr 1, 1992·Molecular Microbiology·Leona D Samson
Jan 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·K TanoS Mitra
Jan 1, 1988·Chemico-biological Interactions·Anthony E PeggM Eileen Dolan
Nov 1, 1988·Carcinogenesis·M Eileen DolanAnthony E Pegg
Oct 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·E L LoechlerJohn M Essigmann
Aug 30, 1984·Biochemical and Biophysical Research Communications·M Eileen DolanAnthony E Pegg
Sep 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·Anthony E PeggR Montesano
Mar 24, 1995·The Journal of Biological Chemistry·L C MyersGregory L Verdine
Jul 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·Y NakatsuruT Ishikawa
Jun 11, 1996·Proceedings of the National Academy of Sciences of the United States of America·F C Christians, Lawrence A Loeb
Mar 1, 1997·American Journal of Industrial Medicine·R B HayesF Oesch
Mar 28, 1997·The Journal of Biological Chemistry·K GoodtzovaAnthony E Pegg
May 1, 1997·Carcinogenesis·Leona D SamsonL J Rasmussen
Feb 28, 1998·The EMBO Journal·K G BerdalE Seeberg
Aug 26, 1998·Proceedings of the National Academy of Sciences of the United States of America·B J GlassnerLeona D Samson
Dec 22, 1999·Nucleic Acids Research·J E WibleyP C Moody
Jan 11, 2000·International Journal of Cancer. Journal International Du Cancer·M R MiddletonGeoffrey P Margison
Apr 18, 2000·Mutation Research·Anthony E Pegg
Jun 30, 2000·Carcinogenesis·L P Encell, Lawrence A Loeb
Jun 16, 2001·Carcinogenesis·H Nilsen, H E Krokan
Dec 18, 2001·Environmental and Molecular Mutagenesis·Sreenivas Kanugula, Anthony E Pegg
Dec 26, 2001·Carcinogenesis·P Karran
Feb 6, 2002·Chembiochem : a European Journal of Chemical Biology·R DamoiseauxKai Johnsson
Mar 14, 2002·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Geoffrey P Margison, Mauro F Santibanez-Koref
Jul 3, 2002·Biochemistry·Kieu X LuuRobert C Moschel
Aug 2, 2002·The Journal of Biological Chemistry·Liping LiuF Peter Guengerich
Oct 4, 2002·Free Radical Biology & Medicine·Yoke W Kow
Dec 7, 2002·Nature Biotechnology·Antje KepplerKai Johnsson
Dec 17, 2002·Oncogene·Barbara Sedgwick, Tomas Lindahl
Dec 24, 2002·The Journal of Biological Chemistry·Joseph J RasimasMichael G Fried
Jan 29, 2003·Biochemistry·Joseph J RasimasAnthony E Pegg
May 3, 2003·Carcinogenesis·Geoffrey P MargisonMauro F Santibáñez Koref
Jun 26, 2003·Journal of the American Chemical Society·Maik KindermannKai Johnsson
Sep 17, 2003·Biochemistry·F Peter GuengerichAnthony E Pegg
Dec 4, 2003·Mutation Research·Philip C HanawaltDaniel R Lloyd
Dec 24, 2003·Protein Science : a Publication of the Protein Society·Joseph J RasimasMichael G Fried
Jan 7, 2004·Investigational New Drugs·Christopher GuerinHenry Brem
Mar 9, 2004·Methods : a Companion to Methods in Enzymology·Antje KepplerKai Johnsson
Apr 2, 2004·Nature Reviews. Cancer·Stanton L Gerson
Jun 29, 2004·Nature Structural & Molecular Biology·Douglas S DanielsJohn A Tainer
Jul 9, 2004·Journal of Medicinal Chemistry·Michael E NelsonRobert C Moschel
Jul 20, 2004·Chemical Research in Toxicology·J Gerardo ValadezF Peter Guengerich
Jan 7, 2005·Journal of Medicinal Chemistry·Guangping WeiRobert C Moschel
Feb 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Sreenivas KanugulaAnthony E Pegg
Mar 30, 2005·Mutation Research·Sharon BarkerDavid Murray
Jun 4, 2005·Chembiochem : a European Journal of Chemical Biology·Alexandre JuilleratKai Johnsson
Jun 21, 2005·Journal of Molecular Biology·Erica M DuguidChuan He
Jul 8, 2005·The Journal of Biological Chemistry·Hong ZangF Peter Guengerich
Oct 18, 2005·Biochemical and Biophysical Research Communications·Suryakant K NitureKalkunte S Srivenugopal
Nov 9, 2005·Molecular Cancer Therapeutics·Kimiko IshiguroAlan C Sartorelli
Nov 16, 2005·Biochemistry·Qingming FangAnthony E Pegg
Jan 24, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lili Liu, Stanton L Gerson
Feb 9, 2006·Chemical Reviews·Yukiko MishinaChuan He
Apr 14, 2006·Nature Reviews. Molecular Cell Biology·Josef Jiricny
Apr 28, 2006·Protein Engineering, Design & Selection : PEDS·Thomas GronemeyerKai Johnsson
May 9, 2006·Nucleic Acids Research·Steven J PearsonGeoffrey P Margison
Oct 20, 2006·The Journal of Biological Chemistry·Jeong-Yun ChoiF Peter Guengerich
Dec 2, 2006·The Journal of Biological Chemistry·Joseph J RasimasMichael G Fried
Dec 21, 2006·Proceedings of the National Academy of Sciences of the United States of America·Joshua J WarrenLorena S Beese
Apr 20, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Olivier L ChinotDominique Figarella-Branger
May 8, 2007·DNA Repair·Anthony E PeggNatalia A Loktionova
May 15, 2007·DNA Repair·Geoffrey P MargisonMauro F Santibanez-Koref
Sep 11, 2007·Biophysical Journal·Tong Zhao, Aaron R Dinner
Oct 25, 2007·International Journal of Cancer. Journal International Du Cancer·Philip A J CrosbieAndrew C Povey
Nov 13, 2007·Biochemical Pharmacology·Qingming FangAnthony E Pegg
Dec 7, 2007·Chemical Research in Toxicology·Stephen S Hecht
Feb 13, 2008·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Aditi HazraDavid J Hunter
Feb 23, 2008·Chemistry & Biology·Arnaud GautierKai Johnsson
Mar 21, 2008·Proceedings of the National Academy of Sciences of the United States of America·Jie HuAaron R Dinner
Apr 5, 2008·International Journal of Cancer. Journal International Du Cancer·James DoeckeAustralian Cancer Study
Aug 21, 2008·Chemical Research in Toxicology·Aley G KalapilaAnthony E Pegg
Jan 7, 2009·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Yanhong LiuMelissa L Bondy
Jan 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joanna KlapaczLeona D Samson
Jan 21, 2009·Cellular and Molecular Life Sciences : CMLS·A P M EkerG T J van der Horst
Jan 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Cheol-Sang HwangAlexander Varshavsky
Feb 4, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jennifer A QuinnHenry S Friedman
Feb 4, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Martin GlasUlrich Herrlinger
Feb 6, 2009·ACS Chemical Biology·Michael BannwarthKai Johnsson
Apr 11, 2009·Journal of Molecular Biology·Claire A AdamsMichael G Fried
May 28, 2009·Environmental and Molecular Mutagenesis·Aley G KalapilaAnthony E Pegg
Jun 2, 2009·Chemical Research in Toxicology·Rachel L LoeberNatalia Tretyakova
Jun 18, 2009·The Journal of Biological Chemistry·Rebecca GuzaNatalia Tretyakova
Jul 30, 2009·Cancer Research·Allen G SchroeringKandace J Williams
Aug 8, 2009·FEMS Microbiology Reviews·Bjørn DalhusMagnar Bjørås
Oct 7, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Michael WellerMarkus Loeffler
Oct 31, 2009·Carcinogenesis·Nidhi ShrivastavJohn M Essigmann
Nov 4, 2009·Chemical Research in Toxicology·Uthpala SeneviratneNatalia Tretyakova
Nov 19, 2009·Mutagenesis·George D D JonesPeter B Farmer
Nov 28, 2009·Mutation Research·Aley G Kalapila, Anthony E Pegg
Dec 10, 2009·Nature Reviews. Neurology·Michael WellerMonika E Hegi
Dec 23, 2009·The Journal of Biological Chemistry·Qingming FangAnthony E Pegg
Feb 6, 2010·DNA Repair·Preeti RajeshDouglas L Pittman
Feb 13, 2010·Neuro-oncology·Athanassios P KyritsisChrissa Sioka
Feb 18, 2010·Mutagenesis·Darragh G McArtGillian R Wasson
Mar 10, 2010·The Journal of Biological Chemistry·James M AraminiGaetano T Montelione
Mar 24, 2010·The Journal of Pharmacology and Experimental Therapeutics·Michiko HoriguchiShigehiro Ohdo
Apr 8, 2010·Science Translational Medicine·Wei WeiLimin Liu
Apr 24, 2010·Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology·Sung-Hsien HuangKan-Tai Hsia
May 21, 2010·Journal of Visualized Experiments : JoVE·Christopher R Provost, Luo Sun
May 27, 2010·Cellular and Molecular Life Sciences : CMLS·Julie L Tubbs, John A Tainer
Jun 15, 2010·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Christian BuschPer Eystein Lønning
Jun 17, 2010·The Journal of Clinical Investigation·Brian C BeardHans-Peter Kiem
Jul 2, 2010·Analytical Chemistry·Mako Kamiya, Kai Johnsson
Jul 27, 2010·Environmental and Molecular Mutagenesis·Richard D Wood
Jul 30, 2010·Journal of Proteome Research·Erin D Michaelson-RichieNatalia Tretyakova
Aug 13, 2010·Nucleic Acids Research·John A BurnsDavid A Scicchitano
Aug 19, 2010·Cellular and Molecular Life Sciences : CMLS·Bernd KainaMarkus Christmann
Aug 21, 2010·Cancer Chemotherapy and Pharmacology·Meredith K ChukElizabeth Fox
Oct 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Gerard MazonRobert P Fuchs
Oct 22, 2010·The Journal of Biological Chemistry·Matthew G PenceF Peter Guengerich
Oct 30, 2010·Current Opinion in Biotechnology·Marlon J Hinner, Kai Johnsson
Nov 3, 2010·The Journal of Physical Chemistry. B·Qianqian HouChengbu Liu
Feb 10, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yuan LinStanton L Gerson
Mar 1, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shuguang LengSteven A Belinsky
Mar 29, 2011·Mutagenesis·Naoki KoyamaMasamitsu Honma

Citations

Jan 13, 2012·Nature Reviews. Cancer·Dragony FuLeona D Samson
Nov 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Oliver J WilkinsonDavid M Williams
Dec 15, 2011·The Journal of Biological Chemistry·Giuseppe PeruginoMaria Ciaramella
Jun 26, 2012·Nucleic Acids Research·Ingrid TessmerMichael G Fried
Jul 20, 2012·Nucleic Acids Research·Manana Melikishvili, Michael G Fried
Aug 12, 2014·Extremophiles : Life Under Extreme Conditions·Antonella VettoneMaria Ciaramella
Jul 30, 2014·Nucleic Acids Research·Ken-ichi HarunaMarkus Englert
Nov 25, 2015·International Journal of Molecular Sciences·Maria TintoréRamon Eritja
May 23, 2012·Mutation Research·Panagiotis GeorgiadisSoterios A Kyrtopoulos
Oct 27, 2015·Extremophiles : Life Under Extreme Conditions·Antonella VettoneGiuseppe Perugino
Nov 4, 2015·Molecular Genetics and Genomics : MGG·Marinalva Martins-PinheiroRenata M A da Costa
Sep 18, 2015·Molecular Pharmaceutics·Karl-Heinz TomaszowskiBernd Kaina
Aug 19, 2015·Journal of Biomedical Science·Thomas C ChenAxel H Schönthal
Jun 3, 2015·Accounts of Chemical Research·Natalia TretyakovaShaofei Ji
Jun 28, 2016·Toxicology and Applied Pharmacology·Jin ChengZhongmin Zou
Aug 3, 2016·Chemical Research in Toxicology·April C L Bostian, Robert L Eoff
Aug 22, 2016·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Guohui SunRugang Zhong
Sep 27, 2013·Chemical Research in Toxicology·Lisa A PetersonAnthony E Pegg
Oct 4, 2016·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Jörg Fahrer, Bernd Kaina
Oct 26, 2016·Biochimica Et Biophysica Acta. General Subjects·Castrese MorroneMaria Ciaramella
Mar 7, 2017·Future Medicinal Chemistry·Guohui SunRugang Zhong
Dec 30, 2016·Basic & Clinical Pharmacology & Toxicology·Arnold GroehlerNatalia Tretyakova
May 10, 2017·Environmental and Molecular Mutagenesis·Nimrat Chatterjee, Graham C Walker
Dec 6, 2017·International Journal of Molecular Sciences·Riccardo MiggianoMaria Ciaramella
Dec 16, 2017·Chembiochem : a European Journal of Chemical Biology·Lauralicia SacreChristopher James Wilds
Jan 30, 2015·Current Protocols in Nucleic Acid Chemistry·Derek K O'FlahertyChristopher James Wilds
Oct 6, 2017·Chembiochem : a European Journal of Chemical Biology·Derek K O'Flaherty, Christopher James Wilds
Oct 4, 2017·Chembiochem : a European Journal of Chemical Biology·Dennis G Gillingham, Basilius Sauter
Jun 14, 2014·American Journal of Clinical Pathology·Ester AlvinoStefania D'Atri
Aug 5, 2014·Chembiochem : a European Journal of Chemical Biology·Francis P McManus, Christopher James Wilds
Nov 16, 2018·Organic & Biomolecular Chemistry·William CoppChristopher James Wilds
Jan 18, 2014·Chembiochem : a European Journal of Chemical Biology·Susith Wickramaratne, Natalia Tretyakova
Sep 2, 2016·Current Protocols in Nucleic Acid Chemistry·Derek K O'Flaherty, Christopher James Wilds
Mar 7, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Reza LatifiLaleh Tahsini
Apr 25, 2020·International Journal of Molecular Sciences·Rosanna MattossovichGiuseppe Perugino
Apr 29, 2020·Cancers·Jehad F AlhmoudMohammed Imad Malki
Apr 30, 2017·Chemical Science·Stefanie N GeigleDennis G Gillingham
Sep 27, 2019·Extremophiles : Life Under Extreme Conditions·Rosanna MattossovichGiuseppe Perugino
Sep 25, 2020·Chemical Society Reviews·Cécile MingardShana J Sturla
Nov 26, 2016·Organic & Biomolecular Chemistry·Derek K O'Flaherty, Christopher James Wilds
Jun 3, 2017·Nucleic Acids Research·Manana Melikishvili, Michael G Fried
Mar 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Riccardo MiggianoMenico Rizzi
Nov 12, 2015·Frontiers in Plant Science·Vasilissa Manova, Damian Gruszka
Jun 16, 2015·Chemistry : a European Journal·Derek K O'Flaherty, Christopher James Wilds
Jun 15, 2013·Angewandte Chemie·Maria TintoréCarme Fàbrega
Nov 12, 2015·Biochemistry. Biokhimii︠a︡·Ya I Buryanov
Jul 14, 2018·Future Medicinal Chemistry·Guohui SunYongzhen Peng
Dec 19, 2019·International Journal of Molecular Sciences·Weinan XiaoRugang Zhong
Nov 9, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Guohui SunYongzhen Peng
Jun 28, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Guohui SunRugang Zhong
May 29, 2015·Biopolymers·Manana Melikishvili, Michael G Fried
Jun 17, 2020·Chemistry : a European Journal·William Copp, Christopher James Wilds
Oct 8, 2020·Frontiers in Genetics·Prabha VermaVineet Gaur

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