Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage.

Sara Giovannini,Josef Jiricny,Simone Repmann,Holger Moch,Marie-Christine Weller

doi:10.1093/nar/gkz624

Sara Giovannini, Josef Jiricny + Show 3 more

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https://doi.org/10.1093/nar/gkz624

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Abstract

Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.

Highlights

The seminal discovery of synthetic lethality between defective homologous recombination (HR) and chemical inhibition of poly(ADP-ribose) polymerases (PARPs) led to the development of clinical Poly(ADP-ribose) polymerases (PARPs) inhibitors (PARPis) that represent a significant breakthrough in the therapy of familial breast and ovarian cancers linked to mutations in the BRCA1/2 genes [1,2,3]
That cleaved AP-sites contribute to PARP inhibitors (PARPis) toxicity could be shown by the synthetic lethality between PARP inhibition and knockdown of XRCC1 [10,30], a cofactor of DNA ligase III that is involved in the final step of base excision repair (BER)
PARPis might be effective in the treatment of other tumour types, alone or in combination with other therapies, and in order to be able to suggest which tumour types might be sensitive to PARPi therapy, it is important to know how this class of drugs works at the molecular level

Summary

Introduction

The seminal discovery of synthetic lethality between defective homologous recombination (HR) and chemical inhibition of poly(ADP-ribose) polymerases (PARPs) led to the development of clinical PARP inhibitors (PARPis) that represent a significant breakthrough in the therapy of familial breast and ovarian cancers linked to mutations in the BRCA1/2 genes [1,2,3]. The cascade of events leading to synthetic lethality is widely believed to be triggered by singlestrand breaks (SSBs). SSBs rapidly activate PARPs, which help facilitate break repair [4,5]. Unrepaired SSBs that persist until S phase collide with replication forks to give rise to one-ended double-strand breaks (DSBs), but these can be rescued by HR [6,7]. Chemicallyinhibited PARPs remain bound at the SSBs and inhibit their repair [8,9,10], which increases the number of toxic DSBs. While normal cells can cope with this increase, DSB accumulation in cells with suboptimal HR, such as those carrying BRCA1/2 mutations, leads to genomic instability and cell death

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