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Published on: April 24, 2021
SURF2 is a MDM2 antagonist in triggering the nucleolar stress response
Sophie Tagnères1, Paulo Espirito Santo1, Julie Radermecker2
1Molecular, Cellular and Developmental Biology unit (MCD), Centre de Biologie Integrative (CBI), Team with an accreditation from the French "Ligue contre le Cancer" organism., University of Toulouse, CNRS, UPS, 118 route de Narbonne, Toulouse, Cedex, France.
Abstract:
Cancer cells rely on high ribosome production to sustain their proliferation rate. Many chemotherapies impede ribosome production which is perceived by cells as "nucleolar stress" (NS), triggering p53-dependent and independent pathways leading to cell cycle arrest and/or apoptosis. The 5S ribonucleoprotein (RNP) particle, a sub-ribosomal particle, is instrumental to NS response. Upon ribosome assembly defects, the 5S RNP accumulates as free form. This free form is able to sequester and inhibit MDM2, thus promoting p53 stabilization. To investigate how cancer cells can resist to NS, here we purify free 5S RNP and uncover an interaction partner, SURF2. Functional characterization of SURF2 shows that its depletion increases cellular sensitivity to NS, while its overexpression promotes their resistance to it. Consistently, SURF2 is overexpressed in many cancers and its expression level is an independent marker of prognosis for adrenocortical cancer. Our data demonstrate that SURF2 buffers free 5S RNP particles, and can modulate their activity, paving the way for the research of new molecules that can finely tune the response to nucleolar stress in the framework of cancer therapies.
Insights
Cancer cells resist nucleolar stress (NS) via SURF2, which buffers free 5S RNP particles. SURF2 overexpression enhances cancer cell resistance to NS, offering potential therapeutic targets for cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Stress Response
Background:
- Cancer cells require high ribosome production for proliferation.
- Chemotherapies induce nucleolar stress (NS) by impeding ribosome production, activating cell death pathways.
- The 5S ribonucleoprotein (RNP) particle plays a key role in the cellular response to NS.
Purpose of the Study:
- To investigate the mechanisms by which cancer cells resist nucleolar stress.
- To identify novel interaction partners of the free 5S RNP particle.
- To explore the functional role of SURF2 in nucleolar stress response and cancer prognosis.
Main Methods:
- Purification of free 5S RNP particles.
- Functional characterization of SURF2 through depletion and overexpression studies.
- Analysis of SURF2 expression in cancer patient data.
Main Results:
- SURF2 was identified as an interaction partner of the free 5S RNP particle.
- SURF2 depletion increased cellular sensitivity to NS, while SURF2 overexpression conferred resistance.
- SURF2 is overexpressed in various cancers and serves as an independent prognostic marker for adrenocortical cancer.
- SURF2 was shown to buffer free 5S RNP particles and modulate their activity.
Conclusions:
- SURF2 plays a critical role in buffering free 5S RNP particles and modulating the cellular response to nucleolar stress.
- SURF2's function in nucleolar stress response suggests its potential as a therapeutic target in cancer.
- Targeting SURF2 or its interaction with 5S RNP may offer new strategies for cancer therapy.
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