A supramodular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA damage.

Full Abstract

The 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.

Author information

Author/s: Lloyd, Janette (J); Chapman, J Ross (JR); Clapperton, Julie A (JA); Haire, Lesley F (LF); Hartsuiker, Edgar (E); Li, Jiejin (J); Carr, Antony M (AM); Jackson, Stephen P (SP); Smerdon, Stephen J (SJ);

Affiliation: Division of Molecular Structure, Medical Research Council National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.

Grants: C20600/A6620 (Agency:Cancer Research UK) ; G0600233 (Agency:Medical Research Council) ; (Agency:Wellcome Trust)

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Cell (Cell), published in United States. (Language: eng)

Reference: 2009-Oct; vol 139 (issue 1) : pp 100-11

Dates: Created 2009/10/06; Completed 2009/10/27;

PMID: 19804756, status: MEDLINE (last retrieval date: 10/27/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Cell. 2009 Oct 2;139(1):25-7. (PMID: 19804750)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Amino Acid Sequence
Cell Cycle Proteins - chemistry
Chromosomal Proteins, Non-Histone - chemistry
Crystallography, X-Ray
DNA Damage
DNA Repair
DNA-Binding Proteins - metabolism
Humans
Models, Molecular

Models, Molecular
Molecular Sequence Data
Mutation
Nuclear Proteins - chemistry
Phosphorylation
Protein Structure, Tertiary
Schizosaccharomyces - chemistry; metabolism
Schizosaccharomyces pombe Proteins - chemistry; metabolism
Sequence Alignment

Associated Chemicals: Cell Cycle Proteins (0) ; Chromosomal Proteins, Non-Histone (0) ; Ctp1 protein, S pombe (0) ; DNA-Binding Proteins (0) ; NBN protein, human (0) ; Nbs1 protein, S pombe (0) ; Nuclear Proteins (0) ; Schizosaccharomyces pombe Proteins (0)

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