1. Cell Biology
Download icon

Bacterial fumarase and L-malic acid are evolutionary ancient components of the DNA damage response

  1. Esti Singer
  2. Yardena BH Silas
  3. Sigal Ben-Yehuda
  4. Ophry Pines  Is a corresponding author
  1. Hebrew University, Israel
Research Article
  • Cited 5
  • Views 1,198
  • Annotations
Cite this article as: eLife 2017;6:e30927 doi: 10.7554/eLife.30927

Abstract

Fumarase is distributed between two compartments of the eukaryotic cell. The enzyme catalyses the reversible conversion of fumaric to L-malic acid in mitochondria as part of the tricarboxylic acid (TCA) cycle, and in the cytosol/nucleus as part of the DNA damage response (DDR). Here we show that fumarase of the model prokaryote Bacillus subtilis (Fum-bc) is induced upon DNA damage, co-localized with the bacterial DNA and is required for the DDR. Fum-bc can substitute for both eukaryotic functions in yeast. Furthermore, we found that the fumarase dependent intracellular signaling of the B. subtilis DDR is achieved via production of L-malic acid, which affects the translation of RecN, the first protein recruited to DNA damage sites. This study provides a different evolutionary scenario in which the dual function of the ancient prokaryotic fumarase, led to its subsequent distribution into different cellular compartments in eukaryotes.

Article and author information

Author details

  1. Esti Singer

    Department of Microbiology and Molecular Genetics, Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Yardena BH Silas

    Department of Microbiology and Molecular Genetics, Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Sigal Ben-Yehuda

    Department of Microbiology and Molecular Genetics, Hebrew University, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Ophry Pines

    Department of Microbiology and Molecular Genetics, Hebrew University, Jerusalem, Israel
    For correspondence
    ophryp@ekmd.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7126-2575

Funding

Israel Science Foundation

  • Ophry Pines

German Israeli Project Cooperation

  • Ophry Pines

CREATE Project of the National Research Foundation of Singapore

  • Ophry Pines

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

Reviewing Editor

  1. Nikolaus Pfanner, University of Freiburg, Germany

Publication history

  1. Received: August 1, 2017
  2. Accepted: November 7, 2017
  3. Accepted Manuscript published: November 15, 2017 (version 1)
  4. Version of Record published: December 1, 2017 (version 2)

Copyright

© 2017, Singer 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

  • 1,198
    Page views
  • 205
    Downloads
  • 5
    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
    Joël Lemière et al.
    Research Article

    During clathrin-mediated endocytosis in eukaryotes, actin assembly is required to overcome large membrane tension and turgor pressure. However, the molecular mechanisms by which the actin machinery adapts to varying membrane tension remain unknown. In addition, how cells reduce their membrane tension when they are challenged by hypotonic shocks remains unclear. We used quantitative microscopy to demonstrate that cells rapidly reduce their membrane tension using three parallel mechanisms. In addition to using their cell wall for mechanical protection, yeast cells disassemble eisosomes to buffer moderate changes in membrane tension on a minute time scale. Meanwhile, a temporary reduction of the rate of endocytosis for 2 to 6 minutes, and an increase in the rate of exocytosis for at least 5 minutes allow cells to add large pools of membrane to the plasma membrane. We built on these results to submit the cells to abrupt increases in membrane tension and determine that the endocytic actin machinery of fission yeast cells rapidly adapts to perform clathrin-mediated endocytosis. Our study sheds light on the tight connection between membrane tension regulation, endocytosis and exocytosis.

    1. Cancer Biology
    2. Cell Biology
    Alvaro Gonzalez Rajal et al.
    Research Advance

    We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.