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Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex

DNA methylation at selective cytosine residues (5mC) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development(1–2). TET enzymes successively convert 5mC to 5hmC, 5fC, and 5caC, the latter two of which are subject to removal by...

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Autores principales: Wang, Lanfeng, Zhou, Yu, Xu, Liang, Xiao, Rui, Lu, Xingyu, Chen, Liang, Chong, Jenny, Li, Hairi, He, Chuan, Fu, Xiang-Dong, Wang, Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521995/
https://www.ncbi.nlm.nih.gov/pubmed/26123024
http://dx.doi.org/10.1038/nature14482
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author Wang, Lanfeng
Zhou, Yu
Xu, Liang
Xiao, Rui
Lu, Xingyu
Chen, Liang
Chong, Jenny
Li, Hairi
He, Chuan
Fu, Xiang-Dong
Wang, Dong
author_facet Wang, Lanfeng
Zhou, Yu
Xu, Liang
Xiao, Rui
Lu, Xingyu
Chen, Liang
Chong, Jenny
Li, Hairi
He, Chuan
Fu, Xiang-Dong
Wang, Dong
author_sort Wang, Lanfeng
collection PubMed
description DNA methylation at selective cytosine residues (5mC) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development(1–2). TET enzymes successively convert 5mC to 5hmC, 5fC, and 5caC, the latter two of which are subject to removal by thymine DNA glycosylase (TDG) in conjunction with base excision repair(1–6). Early reports indicate that 5fC and 5caC could be stably detected on enhancers, promoters, and gene bodies with distinct effects on gene expression, but the mechanisms have remained elusive(7,8). Here we determined the X-ray crystal structure of elongating Pol II in complex with DNA template containing oxidized 5-methylcytosines (oxi-mCs), revealing specific hydrogen bonds between the 5-carboxyl group of 5caC and the conserved epi-DNA recognition loop in the polymerase. This causes a positional shift for incoming NTP thus compromising nucleotide addition. To test the in vivo significance of this structural insight, we determined the global effect of increased 5fC/5caC levels on transcription, finding that such DNA modifications indeed retarded Pol II elongation on gene bodies. These results demonstrate the functional impact of oxi-mCs on gene expression and suggest a novel role for Pol II to function as a specific and direct epigenetic sensor during transcription elongation.
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spelling pubmed-45219952016-01-30 Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex Wang, Lanfeng Zhou, Yu Xu, Liang Xiao, Rui Lu, Xingyu Chen, Liang Chong, Jenny Li, Hairi He, Chuan Fu, Xiang-Dong Wang, Dong Nature Article DNA methylation at selective cytosine residues (5mC) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development(1–2). TET enzymes successively convert 5mC to 5hmC, 5fC, and 5caC, the latter two of which are subject to removal by thymine DNA glycosylase (TDG) in conjunction with base excision repair(1–6). Early reports indicate that 5fC and 5caC could be stably detected on enhancers, promoters, and gene bodies with distinct effects on gene expression, but the mechanisms have remained elusive(7,8). Here we determined the X-ray crystal structure of elongating Pol II in complex with DNA template containing oxidized 5-methylcytosines (oxi-mCs), revealing specific hydrogen bonds between the 5-carboxyl group of 5caC and the conserved epi-DNA recognition loop in the polymerase. This causes a positional shift for incoming NTP thus compromising nucleotide addition. To test the in vivo significance of this structural insight, we determined the global effect of increased 5fC/5caC levels on transcription, finding that such DNA modifications indeed retarded Pol II elongation on gene bodies. These results demonstrate the functional impact of oxi-mCs on gene expression and suggest a novel role for Pol II to function as a specific and direct epigenetic sensor during transcription elongation. 2015-06-29 2015-07-30 /pmc/articles/PMC4521995/ /pubmed/26123024 http://dx.doi.org/10.1038/nature14482 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Lanfeng
Zhou, Yu
Xu, Liang
Xiao, Rui
Lu, Xingyu
Chen, Liang
Chong, Jenny
Li, Hairi
He, Chuan
Fu, Xiang-Dong
Wang, Dong
Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex
title Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex
title_full Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex
title_fullStr Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex
title_full_unstemmed Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex
title_short Molecular Basis for 5-Carboxycytosine Recognition by RNA Polymerase II Elongation Complex
title_sort molecular basis for 5-carboxycytosine recognition by rna polymerase ii elongation complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521995/
https://www.ncbi.nlm.nih.gov/pubmed/26123024
http://dx.doi.org/10.1038/nature14482
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