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Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair

R Scott Williams1, Gerald E Dodson, Oliver Limbo

  • 1Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Cell
|October 7, 2009
PubMed

Insights

The Nijmegen breakage syndrome 1 (Nbs1) protein

Area of Science:

  • Molecular Biology
  • Genetics
  • Structural Biology

Background:

  • The Mre11-Rad50-Nbs1 (MRN) complex, including the Nbs1 subunit, is crucial for maintaining genome integrity.
  • Nbs1 coordinates DNA double-strand break (DSB) repair and checkpoint signaling through interactions with ATM, MDC1, and Sae2/Ctp1/CtIP.
  • The precise structural basis for these interactions and Nbs1's role in recruiting repair factors has remained largely undefined.

Purpose of the Study:

  • To elucidate the structural features of Nbs1 and its interactions with key DNA repair proteins.
  • To understand the molecular mechanisms underlying Nbs1's function in DSB repair and genome stability.
  • To investigate the structural basis of Nijmegen breakage syndrome mutations.

Main Methods:

  • X-ray crystallography and small-angle X-ray scattering (SAXS) to determine Nbs1 structures.
  • Genetic and biochemical analyses to study Nbs1-Ctp1 complex formation and function.
  • Structural analysis of the Nbs1-Ctp1 complex.

Main Results:

  • Defined the fused, extended FHA-BRCT(1)-BRCT(2) domain structure of Nbs1, linked to Mre11 and ATM binding motifs.
  • Revealed that Nbs1 recruits phosphorylated Ctp1 to DSBs via FHA domain interaction with a Ctp1 pThr-Asp motif.
  • Identified an extensive FHA-BRCT interface, a bipartite MDC1-binding scaffold, and a conformational switch in Nbs1, with implications for Nijmegen breakage syndrome mutations.

Conclusions:

  • Structural insights into Nbs1 reveal its mechanism for recruiting Ctp1 to DSBs.
  • The flexible Nbs1 arm tethering Ctp1 suggests localized DNA end processing and homologous recombination.
  • Understanding Nbs1 structure and function provides insights into genome stability and Nijmegen breakage syndrome.

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