Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with<i>MORC2</i>mutations

Hyun, Young Se; Hong, Young Bin; Choi, Byung‐Ok; Chung, Ki Wha

doi:10.1093/brain/aww082

Cited by 33 publications

(55 citation statements)

References 12 publications

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“…4B). The latter interactions are especially notable since a number of recent studies have shown that the R252W mutation causes Charcot-Marie-Tooth (CMT) disease 15,16,19,20 . We recently demonstrated that this mutation causes hyperactivation of HUSH-dependent epigenetic silencing 4 , leading to enhanced and accelerated re-repression of the GFP reporter in our functional assay.…”

Section: The Cw Domain Has a Regulatory Role In The Hush Effector Actmentioning

confidence: 99%

“…5A). MORC2(1-603) bearing CMT mutation R252W 15,16,19,20 showed a small decrease in the rate of ATP hydrolysis. In contrast, SMA mutation T424R 18,21 increased ATPase activity approximately threefold.…”

Section: Disease Mutations Modulate the In Vitro And In Vivo Activitimentioning

confidence: 99%

“…Exome sequencing data from patients with genetically unsolved neuropathies have recently reported missense mutations in the ATPase module of the MORC2 gene [15][16][17][18][19][20][21][22] . A range of symptoms have been detailed, all subject to autosomal dominant inheritance, with a complex genotype-phenotype correlation.…”

Section: Introductionmentioning

confidence: 99%

“…Several reports described Charcot-Marie-Tooth (CMT) disease in families carrying MORC2 mutations including R252W (most commonly) 15,16,19,20 : patients presented in the first or second decade with distal weakness that spread proximally, usually accompanied by signs of CNS involvement. Two other mutations, S87L and T424R, have been reported to cause congenital or infantile onset of neuropathies 15,18,20,21 . Severe spinal muscular atrophy (SMA) with primary involvement of proximal muscles and progressive cerebellar atrophy was detailed in patients with the T424R mutation 18,21 , while diagnosis of patients with the S87L mutation was CMT with SMA-like features 15,20 .…”

Section: Introductionmentioning

confidence: 99%

“…Two other mutations, S87L and T424R, have been reported to cause congenital or infantile onset of neuropathies 15,18,20,21 . Severe spinal muscular atrophy (SMA) with primary involvement of proximal muscles and progressive cerebellar atrophy was detailed in patients with the T424R mutation 18,21 , while diagnosis of patients with the S87L mutation was CMT with SMA-like features 15,20 . We recently showed that the CMT-associated MORC2 mutation R252W hyperactivates HUSHmediated epigenetic silencing in neuronal cells 4 .…”

Section: Introductionmentioning

confidence: 99%

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Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Douse

Bloor

et al. 2017

Preprint

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Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the HUSH complex. Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled coil insertion absent in other GHKL ATPases. We find that dimerization and DNA binding of the MORC2 ATPase module transduce HUSH-dependent silencing. Disease mutations change the dynamics of dimerization by distinct structural mechanisms: destabilizing the ATPase-CW module, trapping the ATP lid or perturbing the dimer interface. These defects lead to modulation of HUSH function, thus providing a molecular basis for understanding MORC2-associated neuropathies.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: The Cw Domain Has a Regulatory Role In The Hush Effector Actmentioning

confidence: 99%

Section: Disease Mutations Modulate the In Vitro And In Vivo Activitimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Douse

Bloor

et al. 2017

Preprint

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Destabilization of microrchidia family CW‐type zinc finger 2 via the cyclin‐dependent kinase 1‐chaperone‐mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule‐targeting agents

Qian

Yang

et al. 2023

Clinical & Translational Med

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Background Microtubule‐targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges. Methods Immunoblotting and RT‐qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein‐protein interaction and protein co‐localization. Results Here, we identified microrchidia family CW‐type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin‐dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone‐mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR. Conclusions Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer.

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HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression

Yang

Sun

Hou

et al. 2022

Clinical & Translational Med

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Aims MORC family CW‐type zinc finger 2 (MORC2), a GHKL‐type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. Methods and Results We report that MORC2 is a relatively stable protein, and the N‐terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real‐time PCR. The N‐terminal but not C‐terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N‐terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone‐mediated autophagy pathway. Consequently, HSP90 inhibitor 17‐AAG effectively blocks the growth and metastatic potential of MORC2‐expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. Conclusion We uncover a previously unknown role for HSP90 N‐terminal inhibitors in promoting MORC2 degradation in a HSP90‐indepentent manner and support the potential application of these inhibitors for treating MORC2‐overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small‐molecule inhibitors of MORC2 for anticancer therapeutic application.

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Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z withMORC2mutations

Cited by 33 publications

References 12 publications

Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Neuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Destabilization of microrchidia family CW‐type zinc finger 2 via the cyclin‐dependent kinase 1‐chaperone‐mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule‐targeting agents

HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression

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