美国宾夕法尼亚大学Ben E. Black、加拿大蒙特利尔大学John M. Pascal等研究人员合作解析了DNA断裂处变构PARP-1滞留的结构基础。这一研究成果于2020年4月3日发表在《科学》杂志上。

Title: Structural basis for allosteric PARP-1 retention on DNA breaks

Author: Levani Zandarashvili, Marie-France Langelier, Uday Kiran Velagapudi, 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

Issue&Volume: 2020/04/03

Abstract: Abstract

The success of poly(ADP-ribose) polymerase–1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.

DOI: 10.1126/science.aax6367

Source: https://science.sciencemag.org/content/368/6486/eaax6367