Publication Date:
2008-05-02
Description:
Single-strand DNA (ssDNA)-binding proteins (SSBs) are ubiquitous and essential for a wide variety of DNA metabolic processes, including DNA replication, recombination, DNA damage detection and repair. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating nucleases, helicases and strand-exchange proteins, activating transcription and mediating protein-protein interactions. In eukaryotes, the major SSB, replication protein A (RPA), is a heterotrimer. Here we describe a second human SSB (hSSB1), with a domain organization closer to the archaeal SSB than to RPA. Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. Upon induction of DNA damage, hSSB1 accumulates in the nucleus and forms distinct foci independent of cell-cycle phase. These foci co-localize with other known repair proteins. In contrast to RPA, hSSB1 does not localize to replication foci in S-phase cells and hSSB1 deficiency does not influence S-phase progression. Depletion of hSSB1 abrogates the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets after ionizing radiation. Cells deficient in hSSB1 exhibit increased radiosensitivity, defective checkpoint activation and enhanced genomic instability coupled with a diminished capacity for DNA repair. These findings establish that hSSB1 influences diverse endpoints in the cellular DNA damage response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Richard, Derek J -- Bolderson, Emma -- Cubeddu, Liza -- Wadsworth, Ross I M -- Savage, Kienan -- Sharma, Girdhar G -- Nicolette, Matthew L -- Tsvetanov, Sergie -- McIlwraith, Michael J -- Pandita, Raj K -- Takeda, Shunichi -- Hay, Ronald T -- Gautier, Jean -- West, Stephen C -- Paull, Tanya T -- Pandita, Tej K -- White, Malcolm F -- Khanna, Kum Kum -- CA10445/CA/NCI NIH HHS/ -- CA123232/CA/NCI NIH HHS/ -- CA92245/CA/NCI NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2008 May 29;453(7195):677-81. doi: 10.1038/nature06883. Epub 2008 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18449195" target="_blank"〉PubMed〈/a〉
Keywords:
Ataxia Telangiectasia Mutated Proteins
;
Cell Cycle/drug effects/radiation effects
;
Cell Cycle Proteins/metabolism
;
*DNA Repair/radiation effects
;
DNA-Binding Proteins/antagonists & inhibitors/genetics/*metabolism
;
*Genomic Instability/radiation effects
;
HeLa Cells
;
Humans
;
Mitochondrial Proteins
;
Phosphorylation
;
Protein Transport/radiation effects
;
Protein-Serine-Threonine Kinases/metabolism
;
Radiation, Ionizing
;
Signal Transduction/drug effects/radiation effects
;
Tumor Suppressor Proteins/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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