TAILIEUCHUNG - Báo cáo khoa học: Substrate specificity and excision kinetics of natural polymorphic variants and phosphomimetic mutants of human 8-oxoguanine-DNA glycosylase

Human 8-oxoguanine-DNA glycosylase (OGG1) efficiently removes muta-genic 8-oxo-7,8-dihydroguanine (8-oxoGua) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine when paired with cytosine in oxidatively damaged DNA. Excision of 8-oxoGua mispaired with adenine may lead to GfiT transversions. | ỊFEBS Journal Substrate specificity and excision kinetics of natural polymorphic variants and phosphomimetic mutants of human 8-oxoguanine-DNA glycosylase Viktoriya S. Sidorenko1 Arthur P. Grollman2 Pawel Jaruga3 4 Miral Dizdaroglu3 and Dmitry O. Zharkov1 5 1 SB RAS Institute of ChemicalBiology and FundamentalMedicine Novosibirsk Russia 2 Laboratory of ChemicalBiology Department of PharmacologicalSciences Stony Brook University NY USA 3 ChemicalScience and Technology Laboratory NationalInstitute of Standards and Technology Gaithersburg MD USA 4 Department of ClinicalBiochemistry Collegium Medicum Nicolaus Copernicus University Bydgoszcz Poland 5 Department of NaturalSciences Novosibirsk State University Russia Keywords 8-oxoguanine DNA damage DNA glycosylase DNA repair substrate specificity Correspondence D. O. Zharkov SB RAS Institute of Chemical Biology and Fundamental Medicine 8 Lavrentiev Ave. Novosibirsk 630090 Russia Fax 7 383 333 3677 Tel 7 383 335 6226 E-mail dzharkov@ Received 7 May 2009 revised 25 June 2009 accepted 14 July 2009 doi Human 8-oxoguanine-DNA glycosylase OGG1 efficiently removes mutagenic 8-oxo-7 8-dihydroguanine 8-oxoGua and 2 6-diamino-4-hydroxy-5-formamidopyrimidine when paired with cytosine in oxidatively damaged DNA. Excision of 8-oxoGua mispaired with adenine may lead to G fi T transversions. Post-translational modifications such as phosphorylation could affect the cellular distribution and enzymatic activity of OGG1. Mutations and polymorphisms of OGG1 may affect the enzymatic activity and have been associated with increased risk of several cancers. In this study we used double-stranded oligodeoxynucleotides containing 8-oxo-Gua Cyt or 8-oxoGua Ade pairs as well as y-irradiated calf thymus DNA to investigate the kinetics and substrate specificity of several known OGG1 polymorphic variants and phosphomimetic Ser fi Glu mutants. Among the polymorphic variants A288V and S326C displayed .

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