Structural basis for allosteric PARP-1 retention on DNA breaks.
Science
; 368(6486)2020 04 03.
Article
em En
| MEDLINE
| ID: mdl-32241924
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Regulação Alostérica
/
Quebras de DNA
/
Inibidores de Poli(ADP-Ribose) Polimerases
/
Poli(ADP-Ribose) Polimerase-1
/
Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos