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Nucleic Acids Research 2004 32(17):5291-5302; doi:10.1093/nar/gkh859
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Published online 5 October 2004

Nucleic Acids Research, Vol. 32 No. 17 © Oxford University Press 2004; all rights reserved

Mutational analysis of the damage-recognition and catalytic mechanism of human SMUG1 DNA glycosylase

Mayumi Matsubara, Tamon Tanaka, Hiroaki Terato, Eiji Ohmae, Shunsuke Izumi, Katsuo Katayanagi and Hiroshi Ide*

Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan

* To whom correspondence should be addressed. Tel/Fax: +81 82 424 7457; Email: ideh{at}hiroshima-u.ac.jp

Received June 14, 2004; Revised August 20, 2004; Accepted September 12, 2004

Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1), previously thought to be a backup enzyme for uracil-DNA glycosylase, has recently been shown to excise 5-hydroxyuracil (hoU), 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU) bearing an oxidized group at ring C5 as well as an uracil. In the present study, we used site-directed mutagenesis to construct a series of mutants of human SMUG1 (hSMUG1), and tested their activity for uracil, hoU, hmU, fU and other bases to elucidate the catalytic and damage-recognition mechanism of hSMUG1. The functional analysis of the mutants, together with the homology modeling of the hSMUG1 structure based on that determined recently for Xenopus laevis SMUG1, revealed the crucial residues for the rupture of the N-glycosidic bond (Asn85 and His239), discrimination of pyrimidine rings through {pi}–{pi} stacking to the base (Phe98) and specific hydrogen bonds to the Watson–Crick face of the base (Asn163) and exquisite recognition of the C5 substituent through water-bridged (uracil) or direct (hoU, hmU and fU) hydrogen bonds (Gly87–Met91). Integration of the present results and the structural data elucidates how hSMUG1 accepts uracil, hoU, hmU and fU as substrates, but not other oxidized pyrimidines such as 5-hydroxycytosine, 5-formylcytosine and thymine glycol, and intact pyrimidines such as thymine and cytosine.


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