1. Biochemistry and Chemical Biology
Download icon

Poly(ADP-ribose) polymerase 1 searches DNA via a 'Monkey Bar' mechanism

  1. Johannes Rudolph  Is a corresponding author
  2. Jyothi Mahadevan
  3. Pamela Dyer
  4. Karolin Luger  Is a corresponding author
  1. University of Colorado, Boulder, United States
Research Article
  • Cited 0
  • Views 450
  • Annotations
Cite as: eLife 2018;7:e37818 doi: 10.7554/eLife.37818

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is both a first responder to DNA damage and a chromatin architectural protein. How PARP1 rapidly finds DNA damage sites in the context of a nucleus filled with undamaged DNA, to which it also binds, is an unresolved question. Here we show that PARP1 association with DNA is diffusion-limited, and release of PARP1 from DNA is promoted by binding of an additional DNA molecule that facilitates a 'monkey bar' mechanism, also known as intersegment transfer. The WGR-domain of PARP1 is essential to this mechanism, and a point mutation (W589A) recapitulates the altered kinetics of the domain deletion. Demonstrating the physiological importance of the monkey bar mechanism for PARP1 function, the W589A mutant accumulates at sites of DNA damage more slowly following laser micro-irradiation than wild-type PARP1. Clinically relevant inhibitors of PARP1 did not alter the rate or mechanism of the release of PARP1 from DNA.

Article and author information

Author details

  1. Johannes Rudolph

    Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, United States
    For correspondence
    Johannes.rudolph@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Jyothi Mahadevan

    Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pamela Dyer

    Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-0142-5073
  4. Karolin Luger

    Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, United States
    For correspondence
    karolin.luger@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-5136-5331

Funding

National Cancer Institute (R01 CA218255)

  • Karolin Luger

Howard Hughes Medical Institute

  • Karolin Luger

University of Colorado Cancer Center Pilot Funding Grant (ST63501792)

  • Karolin Luger

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

Reviewing Editor

  1. Wolf-Dietrich Heyer, Reviewing Editor, University of California, Davis, United States

Publication history

  1. Received: April 24, 2018
  2. Accepted: August 3, 2018
  3. Accepted Manuscript published: August 8, 2018 (version 1)

Copyright

© 2018, Rudolph 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

  • 450
    Page views
  • 108
    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. Biochemistry and Chemical Biology
    Jackie Lang et al.
    Research Article
    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Michael Luke Carlson et al.
    Tools and Resources