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...

Full description

Saved in:
Bibliographic Details
Published in:Cell death & disease 2022-06, Vol.13 (6), p.546-546, Article 546
Main Authors: Shih, Hsueh-Tzu, Chen, Wei-Yi, Wang, Hsin-Yen, Chao, Tung, Huang, Hsien-Da, Chou, Chih-Hung, Chang, Zee-Fen
Format: Article
Language:English
Subjects:
13/1
13/106
13/109
13/44
13/89
14/19
14/63
38/22
38/23
38/43
38/77
42/70
45
45/90
631/337/1427/2122
631/337/176/1988
692/699/249/2512
82/80
82/83
Animals
Antibodies
Beaks
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Centromere - genetics
Centromere - metabolism
Chromosomes
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA - metabolism
DNA damage
DNA Damage - genetics
DNA Methylation
DNA methyltransferase
DNA Methyltransferase 3B
DNA repair
DNA sequencing
Genomes
Genomic instability
Immunodeficiency
Immunologic Deficiency Syndromes - genetics
Immunologic Deficiency Syndromes - metabolism
Immunology
Life Sciences
Mutation
Nucleotide sequence
p53 Protein
R-Loop Structures
R-loops
Satellite DNA
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-022-04989-1