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DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage

This study used DNA methyltransferase 3b (DNMT3b) knockout cells and the functional loss of DNMT3b mutation in immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) cells to understand how DNMT3b dysfunction causes genome instability. We demonstrated that R-loops contribute to DNA...

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Autores principales: Shih, Hsueh-Tzu, Chen, Wei-Yi, Wang, Hsin-Yen, Chao, Tung, Huang, Hsien-Da, Chou, Chih-Hung, Chang, Zee-Fen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187704/
https://www.ncbi.nlm.nih.gov/pubmed/35688824
http://dx.doi.org/10.1038/s41419-022-04989-1
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author Shih, Hsueh-Tzu
Chen, Wei-Yi
Wang, Hsin-Yen
Chao, Tung
Huang, Hsien-Da
Chou, Chih-Hung
Chang, Zee-Fen
author_facet Shih, Hsueh-Tzu
Chen, Wei-Yi
Wang, Hsin-Yen
Chao, Tung
Huang, Hsien-Da
Chou, Chih-Hung
Chang, Zee-Fen
author_sort Shih, Hsueh-Tzu
collection PubMed
description This study used DNA methyltransferase 3b (DNMT3b) knockout cells and the functional loss of DNMT3b mutation in immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) cells to understand how DNMT3b dysfunction causes genome instability. We demonstrated that R-loops contribute to DNA damages in DNMT3b knockout and ICF cells. More prominent DNA damage signal in DNMT3b knockout cells was due to the loss of DNMT3b expression and the acquirement of p53 mutation. Genome-wide ChIP-sequencing mapped DNA damage sites at satellite repetitive DNA sequences including (peri-)centromere regions. However, the steady-state levels of (peri-)centromeric R-loops were reduced in DNMT3b knockout and ICF cells. Our analysis indicates that XPG and XPF endonucleases-mediated cleavages remove (peri-)centromeric R-loops to generate DNA beaks, causing chromosome instability. DNMT3b dysfunctions clearly increase R-loops susceptibility to the cleavage process. Finally, we showed that DNA double-strand breaks (DSBs) in centromere are probably repaired by error-prone end-joining pathway in ICF cells. Thus, DNMT3 dysfunctions undermine the integrity of centromere by R-loop-mediated DNA damages and repair.
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spelling pubmed-91877042022-06-12 DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage Shih, Hsueh-Tzu Chen, Wei-Yi Wang, Hsin-Yen Chao, Tung Huang, Hsien-Da Chou, Chih-Hung Chang, Zee-Fen Cell Death Dis Article This study used DNA methyltransferase 3b (DNMT3b) knockout cells and the functional loss of DNMT3b mutation in immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) cells to understand how DNMT3b dysfunction causes genome instability. We demonstrated that R-loops contribute to DNA damages in DNMT3b knockout and ICF cells. More prominent DNA damage signal in DNMT3b knockout cells was due to the loss of DNMT3b expression and the acquirement of p53 mutation. Genome-wide ChIP-sequencing mapped DNA damage sites at satellite repetitive DNA sequences including (peri-)centromere regions. However, the steady-state levels of (peri-)centromeric R-loops were reduced in DNMT3b knockout and ICF cells. Our analysis indicates that XPG and XPF endonucleases-mediated cleavages remove (peri-)centromeric R-loops to generate DNA beaks, causing chromosome instability. DNMT3b dysfunctions clearly increase R-loops susceptibility to the cleavage process. Finally, we showed that DNA double-strand breaks (DSBs) in centromere are probably repaired by error-prone end-joining pathway in ICF cells. Thus, DNMT3 dysfunctions undermine the integrity of centromere by R-loop-mediated DNA damages and repair. Nature Publishing Group UK 2022-06-11 /pmc/articles/PMC9187704/ /pubmed/35688824 http://dx.doi.org/10.1038/s41419-022-04989-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Shih, Hsueh-Tzu
Chen, Wei-Yi
Wang, Hsin-Yen
Chao, Tung
Huang, Hsien-Da
Chou, Chih-Hung
Chang, Zee-Fen
DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage
title DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage
title_full DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage
title_fullStr DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage
title_full_unstemmed DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage
title_short DNMT3b protects centromere integrity by restricting R-loop-mediated DNA damage
title_sort dnmt3b protects centromere integrity by restricting r-loop-mediated dna damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187704/
https://www.ncbi.nlm.nih.gov/pubmed/35688824
http://dx.doi.org/10.1038/s41419-022-04989-1
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