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. © 2010 Smeenk et al.

Smeenk, G., Wiegant, W., Vrolijk, H., Solari, A., Pastink, A., Van Attikum, H. (2010). The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. THE JOURNAL OF CELL BIOLOGY, 190(5), 741-749 [10.1083/jcb.201001048].

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

SOLARI, ALDO;
2010

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. © 2010 Smeenk et al.
Articolo in rivista - Articolo scientifico
DNA Damage; DNA Repair; Adenosine Triphosphatases; Transfection; RNA Interference; Ubiquitin; Chromatin Assembly and Disassembly; Humans; Cell Line, Tumor; Chromosomes; Histones; Cell Survival; DNA Breaks, Double-Stranded; Signal Transduction; Chromatin; Comet Assay; RNA, Small Interfering; Nucleosomes;
English
2010
190
5
741
749
none
Smeenk, G., Wiegant, W., Vrolijk, H., Solari, A., Pastink, A., Van Attikum, H. (2010). The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. THE JOURNAL OF CELL BIOLOGY, 190(5), 741-749 [10.1083/jcb.201001048].
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/21066
Citazioni
  • Scopus 192
  • ???jsp.display-item.citation.isi??? 185
Social impact