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A supramodular FHA/BRCT-Repeat architecture mediates Nbs1 adaptor function in response to DNA damage
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posted on 2023-06-08, 00:30 authored by Janette Lloyd, J. Ross Chapman, Julie A. Clapperton, Lesley F. Haire, Edgar Hartsuiker, Jiejin Li, Antony CarrAntony Carr, Stephen P. Jackson, Stephen J. SmerdonThe Mre11/Rad50/Nbs1 protein complex plays central enzymatic and signaling roles in the DNA-damage response. Nuclease (Mre11) and scaffolding (Rad50) components of MRN have been extensively characterized, but the molecular basis of Nbs1 function has remained elusive. Here, we present a 2.3A crystal structure of the N-terminal region of fission yeast Nbs1, revealing an unusual but conserved architecture in which the FHA- and BRCT-repeat domains structurally coalesce. We demonstrate that diphosphorylated pSer-Asp-pThr-Asp motifs, recently identified as multicopy docking sites within Mdc1, are evolutionarily conserved Nbs1 binding targets. Furthermore, we show that similar phosphomotifs within Ctp1, the fission yeast ortholog of human CtIP, promote interactions with the Nbs1 FHA domain that are necessary for Ctp1-dependent resistance to DNA damage. Finally, we establish that human Nbs1 interactions with Mdc1 occur through both its FHA- and BRCT-repeat domains, suggesting how their structural and functional interdependence underpins Nbs1 adaptor functions in the DNA-damage response.
History
Publication status
- Published
Journal
CellISSN
0092-8674Publisher
ElsevierExternal DOI
Issue
1Volume
139Page range
100-111Pages
12.0Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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