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Dynamics of endogenous PARP1 and PARP2 during DNA damage revealed by live-cell single-molecule imaging

View ORCID ProfileJyothi Mahadevan, View ORCID ProfileAsmita Jha, View ORCID ProfileJohannes Rudolph, View ORCID ProfileSamuel Bowerman, View ORCID ProfileDomenic Narducci, View ORCID ProfileAnders S Hansen, View ORCID ProfileKarolin Luger
doi: https://doi.org/10.1101/2022.03.12.484081
Jyothi Mahadevan
1Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309
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Asmita Jha
2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Johannes Rudolph
1Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309
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Samuel Bowerman
1Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309
3Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80309
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Domenic Narducci
2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Anders S Hansen
2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Karolin Luger
1Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309
3Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80309
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  • For correspondence: karolin.luger@colorado.edu
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Summary/Abstract

PARP1 contributes to genome architecture and DNA damage repair through its dynamic association with chromatin. PARP1 and PARP2 (PARP1/2) recognize damaged DNA and recruit the DNA repair machinery. Using single molecule microscopy in live cells, we monitored the movement of PARP1/2 on undamaged and damaged chromatin. We identify two classes of freely diffusing PARP1/2 and two classes of bound PARP1/2. The majority (> 60%) of PARP1/2 diffuse freely in both undamaged and damaged nuclei and in the presence of inhibitors of PARP1/2 used for cancer therapy (PARPi). Laser induced DNA damage results in a small fraction of slowly diffusing PARP1 and PARP2 to become transiently bound. Treatment of cells with PARPi in the presence of DNA damage causes subtle changes in the dynamics of bound PARP1/2, in contrast to bulk studies that suggest PARP trapping. Our results imply that next-generation PARPi could specifically target the small fraction of DNA-bound PARP1/2.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 12, 2022.
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Dynamics of endogenous PARP1 and PARP2 during DNA damage revealed by live-cell single-molecule imaging
Jyothi Mahadevan, Asmita Jha, Johannes Rudolph, Samuel Bowerman, Domenic Narducci, Anders S Hansen, Karolin Luger
bioRxiv 2022.03.12.484081; doi: https://doi.org/10.1101/2022.03.12.484081
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Dynamics of endogenous PARP1 and PARP2 during DNA damage revealed by live-cell single-molecule imaging
Jyothi Mahadevan, Asmita Jha, Johannes Rudolph, Samuel Bowerman, Domenic Narducci, Anders S Hansen, Karolin Luger
bioRxiv 2022.03.12.484081; doi: https://doi.org/10.1101/2022.03.12.484081

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