别构 PARP-1 保留在 DNA 断裂处的结构基础。
Structural basis for allosteric PARP-1 retention on DNA breaks.
机构信息
Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Département de Biochimie and Médecine Moléculaire, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
出版信息
Science. 2020 Apr 3;368(6486). doi: 10.1126/science.aax6367.
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.
摘要
聚（ADP-核糖）聚合酶 1（PARP-1）抑制剂（PARPi）在癌症治疗中的成功与其在 DNA 断裂部位捕获 PARP-1 的能力有关。尽管不同形式的 PARPi 均靶向酶的催化中心，但它们捕获 PARP-1 的能力存在差异。我们发现几种结构不同的 PARPi 驱动 PARP-1 的变构作用，以促进从 DNA 断裂处释放。其他抑制剂驱动变构作用以保留 PARP-1 在 DNA 断裂处。此外，我们生成了一种新的 PARPi 化合物，将变构促进释放的化合物转化为变构促进保留的化合物，并提高其杀死癌细胞的能力。这些进展与 PARP-1 捕获是可取还是不可取的临床应用相关。
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2
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Mol Cancer Res. 2019 Feb;17(2):409-419. doi: 10.1158/1541-7786.MCR-18-0138. Epub 2018 Nov 14.
3
Synthetic lethal therapies for cancer: what's next after PARP inhibitors?
Nat Rev Clin Oncol. 2018 Sep;15(9):564-576. doi: 10.1038/s41571-018-0055-6.
4
Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets.
Nat Commun. 2018 May 22;9(1):2016. doi: 10.1038/s41467-018-04466-4.
5
Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance.
Nat Commun. 2018 May 10;9(1):1849. doi: 10.1038/s41467-018-03917-2.
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7
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