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Title: Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC

Abstract

DNA glycosylases preserve genome integrity and define the specificity of the base excision repair pathway for discreet, detrimental modifications, and thus, the mechanisms by which glycosylases locate DNA damage are of particular interest. Bacterial AlkC and AlkD are specific for cationic alkylated nucleobases and have a distinctive HEAT-like repeat (HLR) fold. AlkD uses a unique non-base-flipping mechanism that enables excision of bulky lesions more commonly associated with nucleotide excision repair. In contrast, AlkC has a much narrower specificity for small lesions, principally N3-methyladenine (3mA). Here, we describe how AlkC selects for and excises 3mA using a non-base-flipping strategy distinct from that of AlkD. A crystal structure resembling a catalytic intermediate complex shows how AlkC uses unique HLR and immunoglobulin-like domains to induce a sharp kink in the DNA, exposing the damaged nucleobase to active site residues that project into the DNA. This active site can accommodate and excise N3-methylcytosine (3mC) and N1-methyladenine (1mA), which are also repaired by AlkB-catalyzed oxidative demethylation, providing a potential alternative mechanism for repair of these lesions in bacteria.

Authors:
ORCiD logo; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Science Foundation (NSF)
OSTI Identifier:
1405021
Resource Type:
Journal Article
Resource Relation:
Journal Name: EMBO Journal; Journal Volume: 36; Journal Issue: (20) ; 10, 2017
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Shi, Rongxin, Mullins, Elwood A., Shen, Xing‐Xing, Lay, Kori T., Yuen, Philip K., David, Sheila S., Rokas, Antonis, and Eichman, Brandt F. Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC. United States: N. p., 2017. Web. doi:10.15252/embj.201797833.
Shi, Rongxin, Mullins, Elwood A., Shen, Xing‐Xing, Lay, Kori T., Yuen, Philip K., David, Sheila S., Rokas, Antonis, & Eichman, Brandt F. Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC. United States. doi:10.15252/embj.201797833.
Shi, Rongxin, Mullins, Elwood A., Shen, Xing‐Xing, Lay, Kori T., Yuen, Philip K., David, Sheila S., Rokas, Antonis, and Eichman, Brandt F. Fri . "Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC". United States. doi:10.15252/embj.201797833.
@article{osti_1405021,
title = {Selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC},
author = {Shi, Rongxin and Mullins, Elwood A. and Shen, Xing‐Xing and Lay, Kori T. and Yuen, Philip K. and David, Sheila S. and Rokas, Antonis and Eichman, Brandt F.},
abstractNote = {DNA glycosylases preserve genome integrity and define the specificity of the base excision repair pathway for discreet, detrimental modifications, and thus, the mechanisms by which glycosylases locate DNA damage are of particular interest. Bacterial AlkC and AlkD are specific for cationic alkylated nucleobases and have a distinctive HEAT-like repeat (HLR) fold. AlkD uses a unique non-base-flipping mechanism that enables excision of bulky lesions more commonly associated with nucleotide excision repair. In contrast, AlkC has a much narrower specificity for small lesions, principally N3-methyladenine (3mA). Here, we describe how AlkC selects for and excises 3mA using a non-base-flipping strategy distinct from that of AlkD. A crystal structure resembling a catalytic intermediate complex shows how AlkC uses unique HLR and immunoglobulin-like domains to induce a sharp kink in the DNA, exposing the damaged nucleobase to active site residues that project into the DNA. This active site can accommodate and excise N3-methylcytosine (3mC) and N1-methyladenine (1mA), which are also repaired by AlkB-catalyzed oxidative demethylation, providing a potential alternative mechanism for repair of these lesions in bacteria.},
doi = {10.15252/embj.201797833},
journal = {EMBO Journal},
number = (20) ; 10, 2017,
volume = 36,
place = {United States},
year = {Fri Oct 20 00:00:00 EDT 2017},
month = {Fri Oct 20 00:00:00 EDT 2017}
}