Covalent binding of uracil DNA glycosylase UdgX to abasic DNA upon uracil excision

Ahn, Woo-Chan and Aroli, Shashanka and Kim, Jin-Hahn and Moon, Jeong Hee and Lee, Ga Seal and Lee, Min-Ho and Sang, Pau Biak and Oh, Byung-Ha and Varshney, Umesh and Woo, Eui-Jeon (2019) Covalent binding of uracil DNA glycosylase UdgX to abasic DNA upon uracil excision. In: NATURE CHEMICAL BIOLOGY, 15 (6). 607+.

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Abstract

Uracil DNA glycosylases (UDGs) are important DNA repair enzymes that excise uracil from DNA, yielding an abasic site. Recently, UdgX, an unconventional UDG with extremely tight binding to DNA containing uracil, was discovered. The structure of UdgX from Mycobacterium smegmatis in complex with DNA shows an overall similarity to that of family 4 UDGs except for a protruding loop at the entrance of the uracil-binding pocket. Surprisingly, H109 in the loop was found to make a covalent bond to the abasic site to form a stable intermediate, while the excised uracil remained in the pocket of the active site. H109 functions as a nucleophile to attack the oxocarbenium ion, substituting for the catalytic water molecule found in other UDGs. To our knowledge, this change from a catalytic water attack to a direct nucleophilic attack by the histidine residue is unprecedented. UdgX utilizes a unique mechanism of protecting cytotoxic abasic sites from exposure to the cellular environment.

Item Type:	Journal Article
Publication:	NATURE CHEMICAL BIOLOGY
Publisher:	NATURE PUBLISHING GROUP
Additional Information:	copyright for this article belongs to NATURE PUBLISHING GROUP
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	13 Mar 2020 08:55
Last Modified:	13 Mar 2020 08:55
URI:	http://eprints.iisc.ac.in/id/eprint/62866

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