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• SURF2 is a new key player in nucleolar stress response through the regulation of 5S RNP/MDM2/p53 axis.

ABSTRACT: Cancer cells are addicted to strong ribosome production to sustain their proliferation rate. Many chemotherapies impede ribosome production which is perceived by cells as "nucleolar stress" (NS), triggering TP53-dependent and independent response pathways leading to cell cycle arrest and/or apoptosis. The 5S RNP particle, a sub-ribosomal particle, is instrumental to NS response. Upon ribosome assembly defects, the 5S RNP accumulate as free form. This free form is able to sequester and inhibit MDM2, thus promoting TP53 stabilization. To investigate how cancer cells could resist to NS, we purified free-5S RNP and uncovered a new partner, SURF2. Functional characterization of this protein shows that SURF2 depletion increases cells sensitivity to NS, while its overexpression promotes their resistance to it. Consistently, SURF2 expression level negatively correlates with the overall survival in some cancers. Our data demonstrate that SURF2 can buffer free-5S RNP particles, and modulate their activity. SURF2 appears as a new regulator of NS response and a key player in both ribosomopathies and oncogenic mechanisms.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Julien Marcoux

LAB HEAD: Julien Marcoux

PROVIDER: PXD047905 | Pride | 2024-09-30

REPOSITORIES: Pride

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			Action	DRS
	F123221.dat	Other
	F123225.dat	Other
	F123226.dat	Other
	F123228.dat	Other
	F123230.dat	Other

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SURF2 is a MDM2 antagonist in triggering the nucleolar stress response

Project description:Cancer cells are addicted to strong 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 response pathways leading to cell cycle arrest and/or apoptosis. The 5S RNP particle, a sub-ribosomal particle, is instrumental to NS response. Upon ribosome assembly defects, the 5S RNP accumulate 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, we purified free-5S RNP and uncovered a new 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 expression level negatively correlates with the overall survival in adrenocortical and head and neck squamous cell carcinomas. Our data demonstrate that SURF2 buffers free-5S RNP particles, and can modulate their activity. SURF2 regulates NS responses, and is a key player in both ribosomopathies and oncogenic mechanisms.

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Project description:In eukaryotes, three of the four ribosomal RNAs (rRNAs), the 5.8S, 18S and 25S/28S rRNAs, are processed from a single pre-rRNA transcript and assembled into ribosomes. The fourth rRNA, the 5S rRNA, is transcribed by RNA polymerase III and is assembled into the 5S ribonucleoprotein particle (5S RNP), containing ribosomal proteins Rpl5/uL18 and Rpl11/uL5, prior to its incorporation into pre-ribosomes. In mammals the 5S RNP is also central regulator of the homeostasis of the tumour suppressor p53. The nucleolar localisation of the 5S RNP and its assembly into pre-ribosomes is performed by a specialised complex composed of Rpf2 and Rrs1 in yeast or Bxdc1 and hRrs1 in humans. Here we report the structural and functional characterisation of the Rpf2-Rrs1 complex alone, in complex with the 5S RNA and within pre-60S ribosomes. We show that the Rpf2-Rrs1 complex contains a specialised 5S RNA E loop binding module, contacts the Rpl5 protein and also contacts the ribosome assembly factor Rsa4 and the 25S RNA. We propose that the Rpf2-Rrs1 complex establishes a network of interactions that guide the incorporation of the 5S RNP in pre-ribosomes in the initial conformation prior to its rotation to form the central protuberance found in the mature large ribosomal subunit.

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Project description:The 5S RNP is assembled from its three components (5S rRNA, Rpl5/uL18, and Rpl11/uL5) before being incorporated into the pre-60S subunit. However, when ribosome synthesis is disturbed, a free 5S RNP can enter the MDM2–p53 pathway to regulate cell cycle and apoptotic signaling. Here we reconstitute and determine the cryo-EM structure of the conserved hexameric 5S RNP with fungal or human factors. This reveals how the nascent 5S rRNA associates with the initial nuclear import complex Syo1–uL18–uL5, and upon further recruitment of two nucleolar factors Rpf2–Rrs1 develops into the 5S RNP precursor that can assemble into the pre-ribosome. In addition, we elucidate the structure of another 5S RNP intermediate, carrying the human ubiquitin ligase Mdm2, which unraveled how this enzyme can be sequestered from its target substrate p53. Our data provide molecular insight into how the 5S RNP can mediate between ribosome biogenesis and cell proliferation.

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Project description:We purified pre60S ribosomes from yeast using Nsa1-FtpA as bait in Tandem Affinity Purification experiments. We tested the depletion of RPF2, using a Galactose-depletion system, to obtain ribosomal particles depleted of 5S RNP complexes. Sample A1: Control group (wild type strain) grown in YPGal; Sample A2: Control group (wild type strain) grown in YPGlu; Sample A3: Control group (Gal::HA-RPF2 strain) grown in YPGal; and Sample A4: Test group (Gal::HA-RPF2) shifted from YPGal to YPGlu for 6 hours to achieve 5S RNP depletion. Sample N1: Purified pre-60S Nsa1-associated with 5S RNP depleted after Sucrose gradient separation; Sample N2: Purified pre-60S Nsa1-associated with 5S RNP reconstituted after Sucrose gradient separation.

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