Structural basis for allosteric PARP-1 retention on DNA breaks

• DOI: 10.1126/science.aax6367
• Publication Date: 2020-04-02T23:05:36Z
• Authors: Levani Zandarashvili; Marie-France Lang...; Uday Kiran Velaga...; Mark A. Hancock; Jamin D. Steffen; Ramya Billur; Zain M. Hannan; Andrew J. Wicks; Dragomir B. Krastev; Stephen J. Pettitt; Christopher J. Lord; Tanaji T. Talele; John M. Pascal; Ben E. Black
• Keywords: PARP inhibitor

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