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

Morgen, Patrick von; Burdová, Kamila; Flower, Thomas G; O’Reilly, Nicola; Boulton, Simon J.; Smerdon, Stephen J.; Macůrek, Libor; Hořejšı́, Zuzana

doi:10.1038/onc.2017.99

Cited by 42 publications

(32 citation statements)

References 37 publications

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“…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. Consistent with the findings, depletion of CK2 resulted in MRE11 destabilization and decreased assembly of the MRN complex, hindering the DNA damage repair processes (von Morgen et al, 2017). We investigated whether compound 5 directly inhibits CK2 activity.…”

Section: Resultssupporting

confidence: 61%

“…DSBs and stalled replication forks (von Morgen et al, 2017). MRE11, NBS1, and RAD50 form the MRN complex that allows recognition of DSBs, activates two major DDR kinases, ataxiatelangiectasia-mutated (ATM) and ataxia-telangiectasia-and Rad3-related, stabilizes ends of broken DNA, and facilitates DNA repair by homologous recombination (HR) and nonhomologous end-joining (Williams et al, 2010;Cannavo and Cejka, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance

Chen

Qin

et al. 2017

J Pharmacol Exp Ther

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Two hybrids of Pt(IV) species were designed and prepared by addition of a chlorambucil unit to the axial positions of the Pt(IV) complexes derived from DN603 and DN604. In vitro studies of two hybrids against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drug resistance. Mechanistic investigation suggested that the potent antitumor activity of compound arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand break (DSB) repair. In nude mice with A549/CDDP xenografts, compound exhibited higher anticancer efficacy than cisplatin and chlorambucil by reversing drug resistance, displayed improved effectiveness, and had no toxicity effects. Overall, compound is a promising drug candidate, which could promote the anticancer activity and reverse drug resistance by attenuating CK2-induced MRN-dependent DSB repair.

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Section: Resultssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance

Chen

Qin

et al. 2017

J Pharmacol Exp Ther

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“…We measured CK2 activity indirectly by using an antibody against the phospho-CK2 substrate (motif pS/pTDXE) to measure the amount of phosphorylated CK2 substrates. This method is widely used in literature to measure kinase activity, such as activity of the following kinases CK2 [ 16 , 49 , 50 , 51 , 52 ], AMPK [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], AMT/ATR [ 64 , 65 , 66 , 67 , 68 , 69 , 70 ], PKA [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ], and PKC [ 77 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Both CK2 knockdown and CX-4945 treatment inhibited the proliferation of CCA cells.…”

Section: Discussionmentioning

confidence: 99%

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Lertsuwan

Sawasdichai

et al. 2018

Cancers

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Cholangiocarcinoma is a disease with a poor prognosis and increasing incidence and hence there is a pressing unmet clinical need for new adjuvant treatments. Protein kinase CK2 (previously casein kinase II) is a ubiquitously expressed protein kinase that is up-regulated in multiple cancer cell types. The inhibition of CK2 activity using CX-4945 (Silmitasertib) has been proposed as a novel treatment in multiple disease settings including cholangiocarcinoma. Here, we show that CX-4945 inhibited the proliferation of cholangiocarcinoma cell lines in vitro. Moreover, CX-4945 treatment induced the formation of cytosolic vacuoles in cholangiocarcinoma cell lines and other cancer cell lines. The vacuoles contained extracellular fluid and had neutral pH, features characteristic of methuosis. In contrast, simultaneous knockdown of both the α and α′ catalytic subunits of protein kinase CK2 using small interfering RNA (siRNA) had little or no effect on the proliferation of cholangiocarcinoma cell lines and failed to induce the vacuole formation. Surprisingly, low doses of CX-4945 increased the invasive properties of cholangiocarcinoma cells due to an upregulation of matrix metallopeptidase 7 (MMP-7), while the knockdown of CK2 inhibited cell invasion. Our data suggest that CX-4945 inhibits cell proliferation and induces cell death via CK2-independent pathways. Moreover, the increase in cell invasion brought about by CX-4945 treatment suggests that this drug might increase tumor invasion in clinical settings.

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“…Given the role of these clients in cell growth and proliferation, it was hypothesized that R2TP mediates some of the tumorigenic effects elicited by HSP90 12 . Newly identified clients involved in DNA damage response corroborate this possibility 13 .…”

Section: Introductionmentioning

confidence: 85%

The RPAP3-Cterminal domain identifies R2TP-like quaternary chaperones

et al. 2018

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R2TP is an HSP90 co-chaperone that assembles important macro-molecular machineries. It is composed of an RPAP3-PIH1D1 heterodimer, which binds the two essential AAA+ATPases RUVBL1/RUVBL2. Here, we resolve the structure of the conserved C-terminal domain of RPAP3, and we show that it directly binds RUVBL1/RUVBL2 hexamers. The human genome encodes two other proteins bearing RPAP3-C-terminal-like domains and three containing PIH-like domains. Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP. This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding. Effects are stronger at 32 °C, suggesting that R2SP could help compensating the lower temperate of testis.

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

Cited by 42 publications

References 37 publications

Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance

Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

The RPAP3-Cterminal domain identifies R2TP-like quaternary chaperones

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