Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria

  1. Alexandre Chojnowski
  2. Peh Fern Ong
  3. Esther SM Wong
  4. John SY Lim
  5. Rafidah A Mutalif
  6. Raju Navasankari
  7. Bamaprasad Dutta
  8. Henry Yang
  9. Yi Y Liow
  10. Siu K Sze
  11. Thomas Boudier
  12. Graham D Wright
  13. Alan Colman
  14. Brian Burke
  15. Colin L Stewart
  16. Oliver Dreesen  Is a corresponding author
  1. Institute of Medical Biology, Singapore
  2. Nanyang Technological University, Singapore
  3. National University of Singapore, Singapore
  4. IPAL UMI 2955, Singapore

Abstract

Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.

Article and author information

Author details

  1. Alexandre Chojnowski

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  2. Peh Fern Ong

    Cellular Ageing, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Esther SM Wong

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. John SY Lim

    Microscopy Unit, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Rafidah A Mutalif

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Raju Navasankari

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Bamaprasad Dutta

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Henry Yang

    Bioinformatics Core, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Yi Y Liow

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  10. Siu K Sze

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  11. Thomas Boudier

    Bioinformatics Institute, IPAL UMI 2955, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  12. Graham D Wright

    Microscopy Unit, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  13. Alan Colman

    Stem Cell Disease Models, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  14. Brian Burke

    Nuclear Dynamics and Architecture, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  15. Colin L Stewart

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  16. Oliver Dreesen

    Cellular Ageing, Institute of Medical Biology, Singapore, Singapore
    For correspondence
    oliver.dreesen@imb.a-star.edu.sg
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Karsten Weis, ETH Zürich, Switzerland

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (140960) of the Institute of Medical Biology, A*STAR, Singapore.

Version history

  1. Received: March 27, 2015
  2. Accepted: August 23, 2015
  3. Accepted Manuscript published: August 27, 2015 (version 1)
  4. Version of Record published: September 11, 2015 (version 2)

Copyright

© 2015, Chojnowski 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

  • 5,466
    views
  • 1,195
    downloads
  • 99
    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. Alexandre Chojnowski
  2. Peh Fern Ong
  3. Esther SM Wong
  4. John SY Lim
  5. Rafidah A Mutalif
  6. Raju Navasankari
  7. Bamaprasad Dutta
  8. Henry Yang
  9. Yi Y Liow
  10. Siu K Sze
  11. Thomas Boudier
  12. Graham D Wright
  13. Alan Colman
  14. Brian Burke
  15. Colin L Stewart
  16. Oliver Dreesen
(2015)
Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria
eLife 4:e07759.
https://doi.org/10.7554/eLife.07759

Share this article

https://doi.org/10.7554/eLife.07759

Further reading

    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression
    Ramona Weber, Chung-Te Chang
    Research Article

    Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.

    1. Chromosomes and Gene Expression
    Marwan Anoud, Emmanuelle Delagoutte ... Jean-Paul Concordet
    Research Article

    Tardigrades are microscopic animals renowned for their ability to withstand extreme conditions, including high doses of ionizing radiation (IR). To better understand their radio-resistance, we first characterized induction and repair of DNA double- and single-strand breaks after exposure to IR in the model species Hypsibius exemplaris. Importantly, we found that the rate of single-strand breaks induced was roughly equivalent to that in human cells, suggesting that DNA repair plays a predominant role in tardigrades’ radio-resistance. To identify novel tardigrade-specific genes involved, we next conducted a comparative transcriptomics analysis across three different species. In all three species, many DNA repair genes were among the most strongly overexpressed genes alongside a novel tardigrade-specific gene, which we named Tardigrade DNA damage Response 1 (TDR1). We found that TDR1 protein interacts with DNA and forms aggregates at high concentration suggesting it may condensate DNA and preserve chromosome organization until DNA repair is accomplished. Remarkably, when expressed in human cells, TDR1 improved resistance to Bleomycin, a radiomimetic drug. Based on these findings, we propose that TDR1 is a novel tardigrade-specific gene conferring resistance to IR. Our study sheds light on mechanisms of DNA repair helping cope with high levels of DNA damage inflicted by IR.