MRE11 stability is regulated by CK2-dependent interaction with R2TP complex

P. V. Von Morgen, K. Burdova, T. G. Flower, N. J. O'Reilly, S. J. Boulton, S. J. Smerdon, L. MacUrek*, Z. Hoøejší

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)
117 Downloads (Pure)


The MRN (MRE11-RAD50-NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations of the MRN complex subunit MRE11 cause the hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. Conversely, the PIH1D1 phospho-binding domain PIH-N is required for association with MRE11 phosphorylated by CK2. Consistent with these findings, depletion of PIH1D1 resulted in MRE11 destabilization and affected DNA-damage repair processes dependent on MRE11. Additionally, mutations of serines 688/689, which abolish PIH1D1 binding, also resulted in decreased MRE11 stability. As depletion of R2TP frequently leads to instability of its substrates and as truncation mutation of MRE11 lacking serines 688/689 leads to decreased levels of the MRN complex both in ATLD patients and an ATLD mouse model, our results suggest that the MRN complex is a novel R2TP complex substrate and that their interaction is regulated by CK2 phosphorylation.

Original languageEnglish
Pages (from-to)4943-4950
Number of pages8
Issue number34
Early online date24 Apr 2017
Publication statusPublished - 24 Aug 2017


  • Animals
  • Apoptosis Regulatory Proteins/metabolism
  • Ataxia Telangiectasia/metabolism
  • Ataxia Telangiectasia Mutated Proteins/metabolism
  • Casein Kinase II/metabolism
  • Cell Nucleus/metabolism
  • DNA Damage/physiology
  • DNA Repair/physiology
  • DNA Repair Enzymes/metabolism
  • DNA-Binding Proteins/metabolism
  • Heat-Shock Proteins/metabolism
  • Humans
  • Mice
  • Mutation/physiology
  • Nuclear Proteins/metabolism
  • Phosphorylation/physiology
  • Protein Binding/physiology
  • RNA Polymerase II/metabolism
  • Ribonucleoproteins, Small Nucleolar/metabolism
  • Serine/metabolism
  • TOR Serine-Threonine Kinases/metabolism

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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