Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG

Two mammalian DNA glycosylases, methyl-CpG binding domain protein 4 (MBD4) and thymine DNA glycosylase (TDG), are involved in active DNA demethylation via the base excision repair pathway. Both MBD4 and TDG excise the mismatch base from G:X, where X is uracil, thymine, and 5-hydroxymethyluracil (5hm...

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Main Author:	Hashimoto, Hideharu
Format:	Online
Language:	English
Published:	The Biophysical Society of Japan (BSJ) 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629659/

id	pubmed-4629659
recordtype	oai_dc
spelling	pubmed-46296592016-08-04 Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG Hashimoto, Hideharu Review Article Two mammalian DNA glycosylases, methyl-CpG binding domain protein 4 (MBD4) and thymine DNA glycosylase (TDG), are involved in active DNA demethylation via the base excision repair pathway. Both MBD4 and TDG excise the mismatch base from G:X, where X is uracil, thymine, and 5-hydroxymethyluracil (5hmU). In addition, TDG excises 5mC oxidized bases i.e. when X is 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) not 5-hydroxymethylcytosine (5hmC). A MBD4 inactive mutant and substrate crystal structure clearly explains how MBD4 glycosylase discriminates substrates: 5mC are not able to be directly excised, but a deamination process from 5mC to thymine is required. On the other hand, TDG is much more complicated; in this instance, crystal structures show that TDG recognizes G:X mismatch DNA containing DNA and G:5caC containing DNA from the minor groove of DNA, which suggested that TDG might recognize 5mC oxidized product 5caC like mismatch DNA. In mutation studies, a N157D mutation results in a more 5caC specific glycosylase, and a N191A mutation inhibits 5caC activity while that when X=5fC or T remains. Here I revisit the recent MBD4 glycos ylase domain co-crystal structures with DNA, as well as TDG glycosylase domain co-crystal structures with DNA in conjunction with its mutation studies. The Biophysical Society of Japan (BSJ) 2014-10-18 /pmc/articles/PMC4629659/ /pubmed/27493500 http://dx.doi.org/10.2142/biophysics.10.63 Text en ©2014 THE BIOPHYSICAL SOCIETY OF JAPAN
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hashimoto, Hideharu
spellingShingle	Hashimoto, Hideharu Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG
author_facet	Hashimoto, Hideharu
author_sort	Hashimoto, Hideharu
title	Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG
title_short	Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG
title_full	Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG
title_fullStr	Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG
title_full_unstemmed	Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG
title_sort	structural and mutation studies of two dna demethylation related glycosylases: mbd4 and tdg
description	Two mammalian DNA glycosylases, methyl-CpG binding domain protein 4 (MBD4) and thymine DNA glycosylase (TDG), are involved in active DNA demethylation via the base excision repair pathway. Both MBD4 and TDG excise the mismatch base from G:X, where X is uracil, thymine, and 5-hydroxymethyluracil (5hmU). In addition, TDG excises 5mC oxidized bases i.e. when X is 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) not 5-hydroxymethylcytosine (5hmC). A MBD4 inactive mutant and substrate crystal structure clearly explains how MBD4 glycosylase discriminates substrates: 5mC are not able to be directly excised, but a deamination process from 5mC to thymine is required. On the other hand, TDG is much more complicated; in this instance, crystal structures show that TDG recognizes G:X mismatch DNA containing DNA and G:5caC containing DNA from the minor groove of DNA, which suggested that TDG might recognize 5mC oxidized product 5caC like mismatch DNA. In mutation studies, a N157D mutation results in a more 5caC specific glycosylase, and a N191A mutation inhibits 5caC activity while that when X=5fC or T remains. Here I revisit the recent MBD4 glycos ylase domain co-crystal structures with DNA, as well as TDG glycosylase domain co-crystal structures with DNA in conjunction with its mutation studies.
publisher	The Biophysical Society of Japan (BSJ)
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629659/
_version_	1613496137021390848

Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG

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