Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA.

Proceedings of the National Academy of Sciences of the United States of America
Atanu MaitiAlexander C Drohat

Abstract

DNA base excision repair is essential for maintaining genomic integrity and for active DNA demethylation, a central element of epigenetic regulation. A key player is thymine DNA glycosylase (TDG), which excises thymine from mutagenic G·T mispairs that arise by deamination of 5-methylcytosine (mC). TDG also removes 5-formylcytosine and 5-carboxylcytosine, oxidized forms of mC produced by Tet enzymes. Recent studies show that the glycosylase activity of TDG is essential for active DNA demethylation and for embryonic development. Our understanding of how repair enzymes excise modified bases without acting on undamaged DNA remains incomplete, particularly for mismatch glycosylases such as TDG. We solved a crystal structure of TDG (catalytic domain) bound to a substrate analog and characterized active-site residues by mutagenesis, kinetics, and molecular dynamics simulations. The studies reveal how TDG binds and positions the nucleophile (water) and uncover a previously unrecognized catalytic residue (Thr197). Remarkably, mutation of two active-site residues (Ala145 and His151) causes a dramatic enhancement in G·T glycosylase activity but confers even greater increases in the aberrant removal of thymine from normal A·T base pairs. T...Continue Reading

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Citations

Sep 26, 2013·Journal of the American Chemical Society·Atanu MaitiAlexander C Drohat
Jan 22, 2013·PloS One·Petra Imhof, Mai Zahran
Dec 1, 2012·Mutation Research·Ashley B SjolundJoann B Sweasy
Sep 12, 2015·Nucleic Acids Research·Shuja S MalikAlexander C Drohat
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May 30, 2015·DNA Repair·Alfonso Bellacosa, Alexander C Drohat
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Aug 9, 2016·Chemical Reviews·Alexander C Drohat, Christopher T Coey
Sep 2, 2016·Nucleic Acids Research·Christopher T CoeyAlexander C Drohat
Sep 10, 2016·The Journal of Physical Chemistry Letters·Hugo GattusoAntonio Monari
Mar 24, 2017·PloS One·Daniel E EylerPatrick J O'Brien
Nov 30, 2018·Nucleic Acids Research·Marina AlexeevaSvein Bjelland
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Oct 4, 2020·Nucleic Acids Research·Namrata KumarBennett Van Houten
Apr 12, 2017·Proceedings of the National Academy of Sciences of the United States of America·Elwood A MullinsBrandt F Eichman
Apr 17, 2018·Nucleic Acids Research·Christopher T Coey, Alexander C Drohat
Apr 24, 2021·The Journal of Organic Chemistry·Allison E Krajewski, Jeehiun K Lee
May 8, 2021·The Biochemical Journal·Hala Ouzon-ShubeitaSeongmin Lee
Mar 8, 2019·Journal of the American Chemical Society·Blaine J DowAlexander C Drohat
May 2, 2019·The Journal of Physical Chemistry. B·Eli NaydenovaChristian Ochsenfeld
Nov 3, 2016·Biochemistry·Lakshmi S PiduguAlexander C Drohat
Nov 7, 2019·Journal of the American Chemical Society·Lakshmi S PiduguAlexander C Drohat

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