1. Cell Biology
Download icon

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin

  1. Fernando R Balestra  Is a corresponding author
  2. Andrés Domínguez-Calvo
  3. Benita Wolf
  4. Coralie Busso
  5. Alizée Buff
  6. Tessa Averink
  7. Marita Lipsanen-Nyman
  8. Pablo Huertas
  9. Rosa M Ríos
  10. Pierre Gönczy  Is a corresponding author
  1. CABIMER-University of Seville, Spain
  2. Swiss Federal Institute of Technology, Switzerland
  3. University of Helsinki, Finland
Research Article
  • Cited 0
  • Views 850
  • Annotations
Cite this article as: eLife 2021;10:e62640 doi: 10.7554/eLife.62640

Abstract

TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity, including in Mulibrey patients.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Fernando R Balestra

    Genome Biology Department, CABIMER-University of Seville, Seville, Spain
    For correspondence
    fernando.balestra@cabimer.es
    Competing interests
    The authors declare that no competing interests exist.
  2. Andrés Domínguez-Calvo

    Genome Biology Department, CABIMER-University of Seville, Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Benita Wolf

    Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5673-4239
  4. Coralie Busso

    Swiss Institute of Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Alizée Buff

    Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Tessa Averink

    Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Marita Lipsanen-Nyman

    Children's Hospital, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  8. Pablo Huertas

    Genome Biology Department, CABIMER-University of Seville, Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1756-4449
  9. Rosa M Ríos

    Cell Dynamics and Signalling, CABIMER-University of Seville, Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Pierre Gönczy

    Swiss Institute of Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne, Switzerland
    For correspondence
    pierre.gonczy@epfl.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6305-6883

Funding

Krebsforschung Schweiz (KFS-3388-02-2014)

  • Pierre Gönczy

Marie Curie Actions (PIEF-GA-2013-629414)

  • Fernando R Balestra

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Fibroblast cultures were established from skin biopsy samples with approval by the Institutional Review Board of the Helsinki University Central Hospital (183/13/03/03/2009). The patients signed an informed consent for the use of fibroblast cultures.

Reviewing Editor

  1. Jens Lüders, Institute for Research in Biomedicine, Spain

Publication history

  1. Received: September 2, 2020
  2. Accepted: January 22, 2021
  3. Accepted Manuscript published: January 25, 2021 (version 1)
  4. Version of Record published: February 8, 2021 (version 2)

Copyright

© 2021, Balestra et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 850
    Page views
  • 162
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Physics of Living Systems
    Manuel Giménez-Andrés et al.
    Research Article

    Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain the targeting of perilipins, the most abundant and specific amphipathic proteins of LDs, which are weakly hydrophobic. A striking example is Plin4, whose gigantic and repetitive AH lacks bulky hydrophobic residues. Using a range of complementary approaches, we show that Plin4 forms a remarkably immobile and stable protein layer at the surface of cellular or in vitro generated oil droplets, and decreases LD size. Plin4 AH stability on LDs is exquisitely sensitive to the nature and distribution of its polar residues. These results suggest that Plin4 forms stable arrangements of adjacent AHs via polar/electrostatic interactions, reminiscent of the organization of apolipoproteins in lipoprotein particles, thus pointing to a general mechanism of AH stabilization via lateral interactions.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Asha Mary Joseph et al.
    Research Article

    Translesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicating Caulobacter and observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of this polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair, as replisome components fail to localize in the absence of NER. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.