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

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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.

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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.
Jyothi Mahadevan

Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, United States

Competing interests
The authors declare that no competing interests exist.
Pamela Dyer

Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0142-5073
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.

"This ORCID iD identifies the author of this article:" 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.

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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.