The Escherichia coli alkA Gene Is Activated to Alleviate Mutagenesis by an Oxidized Deoxynucleoside

• Published in: Frontiers in microbiology Vol. 11; p. 263
• Main Authors: Grøsvik, Kristin, Tesfahun, Almaz Nigatu, Muruzábal-Lecumberri, Izaskun, Haugland, Gyri Teien, Leiros, Ingar, Ruoff, Peter, Kvaløy, Jan Terje, Knævelsrud, Ingeborg, Ånensen, Hilde, Alexeeva, Marina, Sato, Kousuke, Matsuda, Akira, Alseth, Ingrun, Klungland, Arne, Bjelland, Svein
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media 25.02.2020; Frontiers Media S.A
• Subjects: 5-formyluracil; AlkA; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; base substitution; Basic medical, dental and veterinary science disciplines: 710; Chemistry: 440; DNA glycosylase; Kjemi: 440; Matematikk og Naturvitenskap: 400; Mathematics and natural science: 400; Medical disciplines: 700; Medisinske Fag: 700; Microbiology; oxidized base repair; VDP; base substitution; DNA glycosylase; oxidized base repair; AlkA; 5-formyluracil
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2020.00263

The cellular methyl donor -adenosylmethionine (SAM) and other endo/exogenous agents methylate DNA bases non-enzymatically into products interfering with replication and transcription. An important product is 3-methyladenine (m A), which in is removed by m A-DNA glycosylase I (Tag) and II (AlkA). The gene is constitutively expressed, while is induced by sub-lethal concentrations of methylating agents. We previously found that AlkA exhibits activity for the reactive oxygen-induced thymine (T) lesion 5-formyluracil (fU) . Here, we provide evidence for AlkA involvement in the repair of oxidized bases by showing that the adenine (A) ⋅ T → guanine (G) ⋅ cytosine (C) mutation rate increased 10-fold in wild-type and cells exposed to 0.1 mM 5-formyl-2'-deoxyuridine (fdU) compared to a wild-type specific reduction of the mutation rate at 0.2 mM fdU, which correlated with gene induction. G⋅C → A⋅T alleviation occurred without induction (at 0.1 mM fdU), correlating with a much higher AlkA efficiency for fU opposite to G than for that to A. The common keto form of fU is the AlkA substrate. Mispairing with G by ionized fU is favored by its exclusion from the AlkA active site.