Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22456334
DOI
10.4161/cc.19978
PII: 19978
Knihovny.cz E-resources
- MeSH
- Tumor Suppressor p53-Binding Protein 1 MeSH
- Benzoates chemistry pharmacology MeSH
- Cell Nucleus drug effects MeSH
- DNA Breaks, Double-Stranded * MeSH
- Furans chemistry pharmacology MeSH
- G1 Phase MeSH
- Intracellular Signaling Peptides and Proteins metabolism MeSH
- Radiation, Ionizing MeSH
- Humans MeSH
- RNA, Small Interfering metabolism MeSH
- Cell Line, Tumor MeSH
- DNA Repair * MeSH
- Pyrazoles chemistry pharmacology MeSH
- RNA Interference MeSH
- Ubiquitin-Activating Enzymes antagonists & inhibitors genetics metabolism MeSH
- Ubiquitination MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 4(4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl)-benzoic acid ethyl ester MeSH Browser
- Tumor Suppressor p53-Binding Protein 1 MeSH
- Benzoates MeSH
- Furans MeSH
- Intracellular Signaling Peptides and Proteins MeSH
- RNA, Small Interfering MeSH
- Pyrazoles MeSH
- TP53BP1 protein, human MeSH Browser
- UBA1 protein, human MeSH Browser
- UBA6 protein, human MeSH Browser
- Ubiquitin-Activating Enzymes MeSH
The cellular DNA damage response (DDR) machinery that maintains genomic integrity and prevents severe pathologies, including cancer, is orchestrated by signaling through protein modifications. Protein ubiquitylation regulates repair of DNA double-strand breaks (DSBs), toxic lesions caused by various metabolic as well as environmental insults such as ionizing radiation (IR). Whereas several components of the DSB-evoked ubiquitylation cascade have been identified, including RNF168 and BRCA1 ubiquitin ligases, whose genetic defects predispose to a syndrome mimicking ataxia-telangiectasia and cancer, respectively, the identity of the apical E1 enzyme involved in DDR has not been established. Here, we identify ubiquitin-activating enzyme UBA1 as the E1 enzyme required for responses to IR and replication stress in human cells. We show that siRNA-mediated knockdown of UBA1, but not of another UBA family member UBA6, impaired formation of both ubiquitin conjugates at the sites of DNA damage and IR-induced foci (IRIF) by the downstream components of the DSB response pathway, 53BP1 and BRCA1. Furthermore, chemical inhibition of UBA1 prevented IRIF formation and severely impaired DSB repair and formation of 53BP1 bodies in G 1, a marker of response to replication stress. In contrast, the upstream steps of DSB response, such as phosphorylation of histone H2AX and recruitment of MDC1, remained unaffected by UBA1 depletion. Overall, our data establish UBA1 as the apical enzyme critical for ubiquitylation-dependent signaling of both DSBs and replication stress in human cells, with implications for maintenance of genomic integrity, disease pathogenesis and cancer treatment.
References provided by Crossref.org
53BP1: pro choice in DNA repair
