Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

ADP-ribosyltransferases promote repair of DNA single strand breaks and disruption of this pathway by Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) is toxic to cells with defects in homologous recombination (HR). Here, we show that this relationship is conserved in the simple eukaryote Dictyostelium and exploit this organism to define mechanisms that drive resistance of the HR-deficient cells to PARPi. Dictyostelium cells disrupted in exonuclease I, a critical factor for HR, are sensitive to PARPi. Deletion of exo1 prevents the accumulation of Rad51 in chromatin induced by PARPi, resulting in DNA damage being channelled through repair by non-homologous end-joining (NHEJ). Inactivation of NHEJ supresses the sensitivity of exo1- cells to PARPi, indicating this pathway drives synthetic lethality and that in its absence alternative repair mechanisms promote cell survival. This resistance is independent of alternate-NHEJ and is instead achieved by re-activation of HR. Moreover, inhibitors of Mre11 restore sensitivity of dnapkcs-exo1- cells to PARPi, indicating redundancy between nucleases that initiate HR can drive PARPi resistance. These data inform on mechanism of PARPi resistance in HR-deficient cells and present Dictyostelium as a convenient genetic model to characterize these pathways.

Original publication

DOI

10.1093/nar/gkx639

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

29/09/2017

Volume

45

Pages

10056 - 10067

Keywords

ADP Ribose Transferases, Benzamides, Clone Cells, Cyclin-Dependent Kinase 8, DNA Damage, Dictyostelium, Drug Resistance, Exodeoxyribonucleases, Gene Deletion, Homologous Recombination, Indoles, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Protozoan Proteins, Quinazolines, Rad51 Recombinase, Recombinant Proteins