Interdependence of the rad50 hook and globular domain functions

Mol Cell. 2015 Feb 5;57(3):479-91. doi: 10.1016/j.molcel.2014.12.018. Epub 2015 Jan 15.

Abstract

Rad50 contains a conserved Zn(2+) coordination domain (the Rad50 hook) that functions as a homodimerization interface. Hook ablation phenocopies Rad50 deficiency in all respects. Here, we focused on rad50 mutations flanking the Zn(2+)-coordinating hook cysteines. These mutants impaired hook-mediated dimerization, but recombination between sister chromatids was largely unaffected. This may reflect that cohesin-mediated sister chromatid interactions are sufficient for double-strand break repair. However, Mre11 complex functions specified by the globular domain, including Tel1 (ATM) activation, nonhomologous end joining, and DNA double-strand break end resection were affected, suggesting that dimerization exerts a broad influence on Mre11 complex function. These phenotypes were suppressed by mutations within the coiled-coil and globular ATPase domains, suggesting a model in which conformational changes in the hook and globular domains are transmitted via the extended coils of Rad50. We propose that transmission of spatial information in this manner underlies the regulation of Mre11 complex functions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatids / metabolism*
  • Chromosomes, Fungal / metabolism
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Endodeoxyribonucleases / metabolism*
  • Exodeoxyribonucleases / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Models, Molecular
  • Mutation
  • Phenotype
  • Protein Conformation
  • Protein Multimerization
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombination, Genetic
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • RAD50 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Protein-Serine-Threonine Kinases
  • TEL1 protein, S cerevisiae
  • Endodeoxyribonucleases
  • Exodeoxyribonucleases
  • MRE11 protein, S cerevisiae