The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex Journal Article
| Authors: | Stracker, T. H.; Morales, M.; Couto, S. S.; Hussein, H.; Petrini, J. H. J. |
| Article Title: | The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex |
| Abstract: | The MRE11 complex (MRE11, RAD50 and NBS1) and the ataxia-telangiectasia mutated (ATM) kinase function in the same DNA damage response pathway to effect cell cycle checkpoint activation and apoptosis. The functional interaction between the MRE11 complex and ATM has been proposed to require a conserved C-terminal domain of NBS1 for recruitment of ATM to sites of DNA damage. Human Nijmegen breakage syndrome (NBS) cells and those derived from multiple mouse models of NBS express a hypomorphic NBS1 allele that exhibits impaired ATM activity despite having an intact C-terminal domain. This indicates that the NBS1 C terminus is not sufficient for ATM function. We derived Nbs1 ΔC/ΔC mice in which the C-terminal ATM interaction domain is deleted. Nbs1ΔC/ΔC cells exhibit intra-S-phase checkpoint defects, but are otherwise indistinguishable from wild-type cells with respect to other checkpoint functions, ionizing radiation sensitivity and chromosome stability. However, multiple tissues of Nbs1 ΔC/ΔC mice showed a severe apoptotic defect, comparable to that of ATM- or CHK2-deficient animals. Analysis of p53 transcriptional targets and ATM substrates showed that, in contrast to the phenotype of Chk2-/- mice, NBS1ΔC does not impair the induction of proapoptotic genes. Instead, the defects observed in Nbs1 ΔC/ΔC result from impaired phosphorylation of ATM targets including SMC1 and the proapoptotic factor, BID. ©2007 Nature Publishing Group. |
| Keywords: | protein phosphorylation; mutation; dna-binding proteins; sequence deletion; nonhuman; protein function; animal cell; chromosome; mouse; phenotype; animals; cell cycle proteins; chromosomal proteins, non-histone; mice; mre11 protein; rad50 protein; allele; dna damage; atp-binding cassette transporters; mus; cell cycle; apoptosis; gene expression; embryo; protein protein interaction; cell line; alleles; enzyme activity; phosphorylation; protein p53; animalia; nibrin; nuclear proteins; dna; amino acid sequence; molecular sequence data; protein-serine-threonine kinases; tumor suppressor proteins; atm protein; ionizing radiation; dna repair enzymes; chromosomal instability; nijmegen breakage syndrome; radiosensitivity; checkpoint kinase 2; protein structure, tertiary; multiprotein complexes; rodent; gene induction; bh3 interacting domain death agonist protein; model; ataxia telangiectasia |
| Journal Title: | Nature |
| Volume: | 447 |
| Issue: | 7141 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2007-05-10 |
| Start Page: | 218 |
| End Page: | 221 |
| Language: | English |
| DOI: | 10.1038/nature05740 |
| PUBMED: | 17429352 |
| PROVIDER: | scopus |
| PMCID: | PMC3089978 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 54" - "Export Date: 17 November 2011" - "CODEN: NATUA" - "Source: Scopus" |
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