Structural basis for the excision repair of alkylation-damaged DNA

Jörg Labahn; Orlando D. Schärer; Alexander Long; Khosro Ezaz-Nikpay; Gregory L. Verdine; Tom E. Ellenberger

doi:10.1016/S0092-8674(00)80103-8

Structural basis for the excision repair of alkylation-damaged DNA

Jörg Labahn
, Orlando D. Schärer
, Alexander Long
, Khosro Ezaz-Nikpay
, Gregory L. Verdine
, Tom E. Ellenberger

Department of Biochemistry & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

234 Scopus citations

Abstract

Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize other closely related lesions. The 1.8 Å crystal structure of the monofunctional DNA glycosylase AlkA (E. coli 3-methyladenine-DNA glycosylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhibitors. We propose that AIkA recognizes electron-deficient methylated bases through π-donor/acceptor interactions involving the electron-rich aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, suggesting the two may employ fundamentally related mechanisms for base excision.

Original language	English
Pages (from-to)	321-329
Number of pages	9
Journal	Cell
Volume	86
Issue number	2
DOIs	https://doi.org/10.1016/S0092-8674(00)80103-8
State	Published - Jul 26 1996

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@article{628d328f563d4941bd5c15d30bb05922,

title = "Structural basis for the excision repair of alkylation-damaged DNA",

abstract = "Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize other closely related lesions. The 1.8 {\AA} crystal structure of the monofunctional DNA glycosylase AlkA (E. coli 3-methyladenine-DNA glycosylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhibitors. We propose that AIkA recognizes electron-deficient methylated bases through π-donor/acceptor interactions involving the electron-rich aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, suggesting the two may employ fundamentally related mechanisms for base excision.",

author = "J{\"o}rg Labahn and Sch{\"a}rer, \{Orlando D.\} and Alexander Long and Khosro Ezaz-Nikpay and Verdine, \{Gregory L.\} and Ellenberger, \{Tom E.\}",

note = "Funding Information: Correspondence should be addressed to G. L. V. or to T. E. E. We thank Craig Ogata and Wayne Hendrickson for assistance with MAD data collection at beamline X-4A, National Synchrotron Light Source (Upton, NY); Alan Friedman for providing local scaling and MAD data analysis programs; and members of the Ellenberger, Verdine, Hogle, and Samson research groups for stimulating discussions. This work was supported by grants from the National Institutes of Health (T. E. E./G. L. V.) and the Lucille P. Markey Charitable Trust (T. E. E.). G. L. V. is a Presidential Young Investigator and T. E. E. is a Lucille P. Markey Scholar in Biomedical Sciences. ",

year = "1996",

month = jul,

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doi = "10.1016/S0092-8674(00)80103-8",

language = "English",

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pages = "321--329",

journal = "Cell",

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T1 - Structural basis for the excision repair of alkylation-damaged DNA

AU - Labahn, Jörg

AU - Schärer, Orlando D.

AU - Long, Alexander

AU - Ezaz-Nikpay, Khosro

AU - Verdine, Gregory L.

AU - Ellenberger, Tom E.

N1 - Funding Information: Correspondence should be addressed to G. L. V. or to T. E. E. We thank Craig Ogata and Wayne Hendrickson for assistance with MAD data collection at beamline X-4A, National Synchrotron Light Source (Upton, NY); Alan Friedman for providing local scaling and MAD data analysis programs; and members of the Ellenberger, Verdine, Hogle, and Samson research groups for stimulating discussions. This work was supported by grants from the National Institutes of Health (T. E. E./G. L. V.) and the Lucille P. Markey Charitable Trust (T. E. E.). G. L. V. is a Presidential Young Investigator and T. E. E. is a Lucille P. Markey Scholar in Biomedical Sciences.

PY - 1996/7/26

Y1 - 1996/7/26

N2 - Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize other closely related lesions. The 1.8 Å crystal structure of the monofunctional DNA glycosylase AlkA (E. coli 3-methyladenine-DNA glycosylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhibitors. We propose that AIkA recognizes electron-deficient methylated bases through π-donor/acceptor interactions involving the electron-rich aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, suggesting the two may employ fundamentally related mechanisms for base excision.

AB - Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize other closely related lesions. The 1.8 Å crystal structure of the monofunctional DNA glycosylase AlkA (E. coli 3-methyladenine-DNA glycosylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhibitors. We propose that AIkA recognizes electron-deficient methylated bases through π-donor/acceptor interactions involving the electron-rich aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, suggesting the two may employ fundamentally related mechanisms for base excision.

UR - https://www.scopus.com/pages/publications/0030602838

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DO - 10.1016/S0092-8674(00)80103-8

M3 - Article

C2 - 8706136

AN - SCOPUS:0030602838

SN - 0092-8674

VL - 86

SP - 321

EP - 329

JO - Cell

JF - Cell

IS - 2

ER -

Structural basis for the excision repair of alkylation-damaged DNA

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