Structural basis for allosteric PARP-1 retention on DNA breaks-Reference-Cited by-同舟云学术

Structural basis for allosteric PARP-1 retention on DNA breaks

Published:2020-04-03 Issue:6486 Volume:368 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Zandarashvili Levani¹,Langelier Marie-France²^ORCID,Velagapudi Uday Kiran³^ORCID,Hancock Mark A.⁴^ORCID,Steffen Jamin D.⁵^ORCID,Billur Ramya¹^ORCID,Hannan Zain M.¹,Wicks Andrew J.⁶^ORCID,Krastev Dragomir B.⁶^ORCID,Pettitt Stephen J.⁶^ORCID,Lord Christopher J.⁶^ORCID,Talele Tanaji T.³^ORCID,Pascal John M.²^ORCID,Black Ben E.¹^ORCID

Affiliation:

1. Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

2. Département de Biochimie and Médecine Moléculaire, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.

3. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA.

4. SPR-MS Facility, McGill University, Montréal, Quebec, Canada.

5. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

6. CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK.

Abstract

DNA death grip Poly(ADP-ribose) polymerase–1 (PARP-1) binds to DNA breaks and recruits DNA repair components. Cancer-killing PARP-1 inhibitor (PARPi) compounds all block the same catalytic site but exhibit vastly different efficacy. Zandarashvili et al. investigated the molecular impact of PARPi binding to PARP-1 (see the Perspective by Slade and Eustermann). Different PARPi molecules perturb PARP-1 allostery in diverse manners: Some drive allostery to promote release of PARP-1 from DNA, and others drive allostery to promote retention. These insights help explain the different efficacies in the clinic and enable conversion of a pro-release, ineffective cancer-killing compound to a pro-retention, more effective PARPi. Science , this issue p. eaax6367 ; see also p. 30

Funder

National Institutes of Health

Breast Cancer Now

Canadian Institutes of Health Research

Cancer Research UK

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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