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PMID: 20805320 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage.

The Journal of cell biology ·Vol. 190 ·No. 5 ·2010-09-06 ·Pages 741-9

Smeenk G, Wiegant WW, Vrolijk H, Solari AP, Pastink A, van Attikum H

Abstract

Cells respond to ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) by orchestrating events that coordinate cell cycle progression and DNA repair. How cells signal and repair DSBs is not yet fully understood. A genome-wide RNA interference screen in Caenorhabditis elegans identified egr-1 as a factor that protects worm cells against IR. The human homologue of egr-1, MTA2 (metastasis-associated protein 2), is a subunit of the nucleosome-remodeling and histone deacetylation (NuRD) chromatin-remodeling complex. We show that knockdown of MTA2 and CHD4 (chromodomain helicase DNA-binding protein 4), the catalytic subunit (adenosine triphosphatase [ATPase]) of NuRD, leads to accumulation of spontaneous DNA damage and increased IR sensitivity. MTA2 and CHD4 accumulate in DSB-containing chromatin tracks generated by laser microirradiation. Directly at DSBs, CHD4 stimulates RNF8/RNF168-dependent formation of ubiquitin conjugates to facilitate the accrual of RNF168 and BRCA1. Finally, we show that CHD4 promotes DSB repair and checkpoint activation in response to IR. Thus, the NuRD chromatin-remodeling complex is a novel regulator of DNA damage responses that orchestrates proper signaling and repair of DSBs.

MeSH Terms
Adenosine Triphosphatases/genetics,metabolism Cell Line, Tumor Cell Survival Chromatin Chromatin Assembly and Disassembly Chromosomes/metabolism Comet Assay DNA Breaks, Double-Stranded DNA Damage DNA Repair Histones/genetics,metabolism Humans Nucleosomes/metabolism RNA Interference RNA, Small Interfering/metabolism,pharmacology Signal Transduction/genetics Transfection Ubiquitin/genetics,metabolism
Chemicals
Chromatin Histones Nucleosomes RNA, Small Interfering Ubiquitin Adenosine Triphosphatases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Smeenk Godelieve
Department of Toxicogenetics, Leiden University Medical Center, Leiden 2300RC, Netherlands.
Wiegant Wouter W
Vrolijk Hans
Solari Aldo P
Pastink Albert
van Attikum Haico
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.201001048
Published
2010-09-06
Epub
2010-00-30
Pages
741-9
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2935570
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.201001048 PMC Full Text View journal details
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