Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism
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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-08-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/37818 |
| _version_ | 1811199385388711936 |
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| author | Johannes Rudolph Jyothi Mahadevan Pamela Dyer Karolin Luger |
| author_facet | Johannes Rudolph Jyothi Mahadevan Pamela Dyer Karolin Luger |
| author_sort | Johannes Rudolph |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T01:47:27Z |
| format | Article |
| id | doaj.art-92f9641209404dd5af956c6260fd1601 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:47:27Z |
| publishDate | 2018-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-92f9641209404dd5af956c6260fd16012022-12-22T03:53:02ZengeLife Sciences Publications LtdeLife2050-084X2018-08-01710.7554/eLife.37818Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanismJohannes Rudolph0https://orcid.org/0000-0003-0230-3323Jyothi Mahadevan1Pamela Dyer2https://orcid.org/0000-0002-0142-5073Karolin Luger3https://orcid.org/0000-0001-5136-5331Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, United StatesDepartment of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, United StatesDepartment of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, United States; Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, United StatesDepartment of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, United States; Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, United StatesPoly(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.https://elifesciences.org/articles/37818protein DNA interactionstopped flow kineticsDNA damagePARP1DNA repair |
| spellingShingle | Johannes Rudolph Jyothi Mahadevan Pamela Dyer Karolin Luger Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism eLife protein DNA interaction stopped flow kinetics DNA damage PARP1 DNA repair |
| title | Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism |
| title_full | Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism |
| title_fullStr | Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism |
| title_full_unstemmed | Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism |
| title_short | Poly(ADP-ribose) polymerase 1 searches DNA via a ‘monkey bar’ mechanism |
| title_sort | poly adp ribose polymerase 1 searches dna via a monkey bar mechanism |
| topic | protein DNA interaction stopped flow kinetics DNA damage PARP1 DNA repair |
| url | https://elifesciences.org/articles/37818 |
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