The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex  

Oleh:

Stracker, Travis H ; Morales, Monica ; Couto, Suzana S ; Hussein, Hussein ; Petrini, John H.J.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: NATURE (keterangan: ada di Proquest) vol. 447 no. 7141 (May 2007), page 218.

Ketersediaan

Perpustakaan FK Nomor Panggil: N01.K.2007.05 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

Lihat Detail Induk

Isi artikel

The MRE11 complex (MRE11, RAD50 and NBS1) and the ataxiatelangiectasia mutated (ATM) kinase function in the same DNA damage response pathway to effect cell cycle checkpoint activation and apoptosis1-3. The functional interaction between the MRE11 complex and ATM has been proposed to require a conserved C-terminal domain of NBSI for recruitment of ATM to sites of DNA damage4,5. Human Nijmegen breakage syndrome (NBS) cells and those derived from multiple mouse models of NBS express a hypomorphic NBS 1 allele that exhibits impaired A TM activity despite having an intact C-terminal domain3,6-ll. This indicates that the NBSI C terminus is not sufficient for ATM function. We derived NbslAClAC mice in which the C-terminal ATM interaction domain is deleted. NbslAc/AC 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 NbslAClAC 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, NBSIAC does not impair the induction of proapoptotic genes. Instead, the defects observed in NbslAClAC result from impaired phosphorylation of ATM targets including SMCI and the proapoptotic factor, BID.

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