SURF2 is a MDM2 antagonist in triggering the nucleolar stress response

Sep 21, 2026

Uploaded by Miles

Cancer cells sustain proliferation through intensified ribosome biogenesis, but many chemotherapies block ribosome production, generating nucleolar stress. Nucleolar stress triggers p53-dependent and p53-independent programs that can arrest the cell cycle and/or induce apoptosis. The 5S ribonucleoprotein particle accumulates in a free form upon assembly defects and sequesters MDM2 to stabilize p53. This work isolates free 5S RNP, identifies SURF2 as an interaction partner, and shows SURF2 depletion sensitizes cells while SURF2 overexpression promotes resistance; SURF2 overexpression correlates with prognosis in adrenocortical cancer.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

SURF2 and nucleolar stress response

Ribosome biogenesis inhibition and nucleolar stress

Free 5S RNP accumulation and MDM2 sequestration

Identifying SURF2 as a partner

Functional impact on sensitivity and resistance

Article [https://doi.org/10.1038/s41467-024-52659-x](https://doi.org/10.1038/s41467-024-52659-x) SURF2 is a MDM2 antagonist in triggering the nucleolar stress response Received: 21 November 2023 | Accepted: 16 September 2024 | | --- | | | | Check for updates | Sophie Tagnères 1, Paulo Espirito Santo1, Julie Radermecker2, Dana Rinaldi1, Carine Froment3,4, Quentin Provost1, Manon Bongers1, Solemne Capeille1, Nick Watkins5, Julien Marcoux 3,4, Pierre-Emmanuel Gleizes 1, Virginie Marcel 2, Célia Plisson-Chastang 1 & Simon Lebaron 1,6 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 freeform. 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 ofSURF2shows 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. Cancers originate from the accumulation of genetic events that allow uncontrolled cell proliferation. Thanks to large-scale sequencing ofthe cancer genome, it is now possible to identify cancer-speciﬁc alterations. This information can then be used for diagnosis but also allows the development of alternative therapeutic approaches for speciﬁc targets1. Although these so-called targeted therapies have proven to be effective, they are also associated with side effects that hinder their advantages. Moreover, drug resistance, induced either by mutation of the speciﬁc target or the activation of alternative survival pathways, is often observed2. Combination therapies are therefore needed to modulate the metabolic circuits that support the proliferation of cancer cells. A key metabolic pathway in cancer cells is the abnormal boost in ribosome synthesis to meet the protein requirements associated with uncontrolled cell growth and proliferation3. The nucleolus is the nuclear sub-compartment where ribosome synthesis begins, and the boost in ribosome synthesis is associated with increased nucleolus size. This phenotype has long been used as a marker of tumor cell aggressiveness3,4. Certain cancer types and cancer cell populations are thus addicted to ribosome synthesis. Nucleolar stress (NS) can be deﬁned as any stress leading to the inhibition of ribosome assembly, a complex and energy-consuming process that begins with the transcription of ribosomal DNA by the speciﬁc RNA polymerase I (Pol I) in the nucleolus5. Under stress, cells reduce ribosome production to conserve energy and stop cell 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. 2Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, CEDEX 08, Lyon, France. 3Institut de Pharmacologie et de Biologie Structurale(IPBS), Universitéde Toulouse, CNRS, UniversitéToulouse III-Paul Sabatier(UPS), Toulouse, France. 4Infrastructure Nationale de Protéomique, ProFI, Toulouse, F

FAQs

What is nucleolar stress (NS) and how does it relate to ribosome biogenesis?

NS is triggered by stress that inhibits ribosome assembly, an energy-consuming process initiated in the nucleolus by RNA polymerase I. Cells reduce ribosome production to conserve energy and stop proliferation.

How do free 5S RNP particles influence MDM2 and p53?

Upon ribosome assembly defects, free 5S RNP accumulates and sequesters/inhibits MDM2, promoting p53 stabilization. This contributes to cell cycle arrest and/or apoptosis.

What role does SURF2 play in the nucleolar stress response?

SURF2 buffers free 5S RNP particles and can modulate their activity. Depleting SURF2 increases cellular sensitivity to NS, whereas overexpressing SURF2 promotes resistance to NS.

Sep 21, 2026

Uploaded by Miles