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MRE11 stability is regulated by CK2-dependent interaction with R2TP complex
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SYSNO ASEP 0487326 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title MRE11 stability is regulated by CK2-dependent interaction with R2TP complex Author(s) von Morgen, Patrick (UMG-J)
Burdová, Kamila (UMG-J)
Flower, T.G. (GB)
O'Reilly, N.J. (GB)
Boulton, S.J. (GB)
Smerdon, S.J. (GB)
Macůrek, Libor (UMG-J) RID, ORCID
Hořejší, Zuzana (UMG-J) RIDNumber of authors 8 Source Title Oncogene. - : Springer - ISSN 0950-9232
Roč. 36, č. 34 (2017), s. 4943-4950Number of pages 8 s. Language eng - English Country GB - United Kingdom Keywords strand break repair ; telangiectasia-like disorder ; rna-polymerase-ii ; clinical presentation ; dna adducts ; phosphorylation ; hsp90 ; protein ; cancer ; cochaperone Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects GA14-34264S GA ČR - Czech Science Foundation (CSF) Institutional support UMG-J - RVO:68378050 UT WOS 000408234400010 DOI 10.1038/onc.2017.99 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2018
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