1. Cell Biology

XAB2 dynamics during DNA damage-dependent transcription inhibition

  1. Lise-Marie Donnio  Is a corresponding author
  2. Elena Cerutti
  3. Charlene Magnani
  4. Damien Neuillet
  5. Pierre-Olivier Mari
  6. Giuseppina Giglia-Mari  Is a corresponding author
  1. CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, France
https://doi.org/10.7554/eLife.77094
Share this article
Cite this article
  1. Lise-Marie Donnio
  2. Elena Cerutti
  3. Charlene Magnani
  4. Damien Neuillet
  5. Pierre-Olivier Mari
  6. Giuseppina Giglia-Mari
(2022)
XAB2 dynamics during DNA damage-dependent transcription inhibition
eLife 11:e77094.
https://doi.org/10.7554/eLife.77094
  2. Download BibTeX
  3. Download .RIS

Abstract

Xeroderma Pigmentosum group A-binding protein 2 (XAB2) is a multi-functional protein playing a critical role in distinct cellular processes including transcription, splicing, DNA repair and mRNA export. In this study, we demonstrate that XAB2 is involved specifically and exclusively in Transcription-Coupled Nucleotide Excision Repair (TC-NER) reactions and solely for RNA Polymerase 2 transcribed genes. Surprisingly, contrary to all the other NER proteins studied so far, XAB2 does not accumulate on the local UV-C damage; on the contrary, it becomes more mobile after damage induction. XAB2 mobility is restored when DNA repair reactions are completed. By scrutinizing from which cellular complex/partner/structure XAB2 is released, we have identified that XAB2 is detached after DNA damage induction from DNA:RNA hybrids, commonly known as R-loops, and from the CSA and XPG proteins. This release contributes to the DNA damage recognition step during TC-NER, as in the absence of XAB2, RNAP2 is blocked longer on UV lesions. Moreover, we also demonstrate that XAB2 has a role in retaining RNAP2 on its substrate without any DNA damage.

Data availability

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

Article and author information

Author details

  1. Lise-Marie Donnio

    Institut NeuroMyogène (INMG), CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
    For correspondence
    lise-marie.donnio@live.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2414-6034

  2. Elena Cerutti

    Institut NeuroMyogène (INMG), CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4644-4817

  3. Charlene Magnani

    Institut NeuroMyogène (INMG), CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.

  4. Damien Neuillet

    Institut NeuroMyogène (INMG), CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.

  5. Pierre-Olivier Mari

    Institut NeuroMyogène (INMG), CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.

  6. Giuseppina Giglia-Mari

    Institut NeuroMyogène (INMG), CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France
    For correspondence
    ambra.mari@univ-lyon1.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2001-1965

Funding

Agence Nationale de la Recherche (ANR-14-CE10-0009)

  • Giuseppina Giglia-Mari

Institut National Du Cancer (PLBIO17-043)

  • Giuseppina Giglia-Mari

Institut National Du Cancer (PLBIO19-126)

  • Giuseppina Giglia-Mari

Ligue Contre le Cancer (218398)

  • Giuseppina Giglia-Mari

Electricité de France (218398)

  • Giuseppina Giglia-Mari

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

Copyright

© 2022, Donnio 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

  • 1,072
    views
  • 235
    downloads
  • 6
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Lise-Marie Donnio
  2. Elena Cerutti
  3. Charlene Magnani
  4. Damien Neuillet
  5. Pierre-Olivier Mari
  6. Giuseppina Giglia-Mari
(2022)
XAB2 dynamics during DNA damage-dependent transcription inhibition
eLife 11:e77094.
https://doi.org/10.7554/eLife.77094

Share this article

https://doi.org/10.7554/eLife.77094

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology

    Stratification of enterochromaffin cells by single-cell expression analysis

    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology
    2. Developmental Biology

    Lens Development: Bringing signaling complexity into focus

    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.