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Insights into DNA damage signaling from the structure of an Mre11:Nbs1 complex
Author(s) -
Hopfner KarlPeter
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb39
Subject(s) - microbiology and biotechnology , dna repair , dna , rad50 , dna damage , chemistry , biology , genetics , dna binding protein , transcription factor , gene
DNA double‐strand breaks (DSBs) are highly cytotoxic, can lead to cancerogenic chromosome aberrations and induce a complex cellular response including DSB signaling, DSB repair or apoptosis. The multifunctional Mre11‐Rad50‐Nbs1 (MRN) complex senses and helps to repair DSBs, but also initiates DSB signaling by recruiting and activating the kinase ataxia‐telangiectasia mutated (ATM). To reveal how MRN initiates DSB signaling, we determined crystal structures of the Schizosaccharomyces pombe Mre11 nuclease dimer and its complex with the Mre11 interacting region of Nbs1. Two Nbs1 polypeptides bind to one Mre11 dimer by stretching around the outsides of its nuclease domains. Remarkably, one of the two Nbs1 additionally binds asymmetrically across the Mre11 dimer interface, opposite the DNA binding groove. This interaction is mediated by highly conserved motifs on both Mre11 and Nbs1 and includes insertion of an Nbs1 phenylalanine between asparagines from each Mre11 protomer. These prominent asparagines are mutated in A‐T like disease suggesting that Nbs1 dependent Mre11 dimer bridging is critical for DSB signaling. Comparison of the Mre11‐Nbs1 complex with our structure of S. pombe Mre11 alone and with previously reported DNA bound archaeal Mre11 suggests a plausible mechanism for DSB signaling.