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Ubiquitin Ligase MARCH5 Regulates Apoptosis through Mediation of Stress-Induced and NOXA-Dependent MCL1 Degradation

View ORCID ProfileSeiji Arai, Sen Chen, Lisha Xie, View ORCID ProfileSteven P. Balk
doi: https://doi.org/10.1101/2020.01.12.903369
Seiji Arai
1Hematology-Oncology Division, Department of Medicine, and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
2Department of Urology, Gunma University Hospital, Maebashi, Gunma, Japan
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Sen Chen
1Hematology-Oncology Division, Department of Medicine, and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
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Lisha Xie
1Hematology-Oncology Division, Department of Medicine, and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
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Steven P. Balk
1Hematology-Oncology Division, Department of Medicine, and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
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  • For correspondence: sbalk@bidmc.harvard.edu
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Abstract

MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 13, 2020.
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Ubiquitin Ligase MARCH5 Regulates Apoptosis through Mediation of Stress-Induced and NOXA-Dependent MCL1 Degradation
Seiji Arai, Sen Chen, Lisha Xie, Steven P. Balk
bioRxiv 2020.01.12.903369; doi: https://doi.org/10.1101/2020.01.12.903369
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Ubiquitin Ligase MARCH5 Regulates Apoptosis through Mediation of Stress-Induced and NOXA-Dependent MCL1 Degradation
Seiji Arai, Sen Chen, Lisha Xie, Steven P. Balk
bioRxiv 2020.01.12.903369; doi: https://doi.org/10.1101/2020.01.12.903369

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