The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2′-deoxycytidine lesions

Abstract

Decitabine (5-aza-2′-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trapping DNA methyltranferases (DNMT) to DNA. We demonstrate for the first time that base excision repair (BER) recognizes 5-azadC-induced lesions in DNA and mediates repair. We find that BER (XRCC1) deficient cells are sensitive to 5-azadC and display an increased amount of DNA single- and double-strand breaks. The XRCC1 protein co-localizes with DNMT1 foci after 5-azadC treatment, suggesting a novel and specific role of XRCC1 in the repair of trapped DNMT1. 5-azadC-induced DNMT foci persist in XRCC1 defective cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. Poly (ADP-ribose) polymerase (PARP) inhibition prevents XRCC1 relocation to DNA damage sites, disrupts XRCC1–DNMT1 co-localization and thereby efficient BER. In a panel of AML cell lines, combining 5-azadC and Olaparib cause synthetic lethality. These data suggest that PARP inhibitors can be used in combination with 5-azadC to improve treatment of MDS and AML.

Repair of DNA Damage Induced by the Cytidine Analog Zebularine Requires ATR and ATM in Arabidopsis

“…a minor fraction of zebularine-induced damage is repaired by NER or SSA, which is also consistent with our HR data. This contrasts with the effects of 5-azacytidine, where NER is the dominant repair pathway in bacteria and humans (Salem et al, 2009;Orta et al, 2014). Because the smc6b mutant was more sensitive to zebularine than to other tested drugs, we suggest that the SMC5-SMC6 complex plays an essential role in the repair of zebularine-induced NPAs in Arabidopsis.…”

The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine

“…Indeed, a recent study has demonstrated that XRCC1 mutant cells, defective in BER, are hypersensitive to aza-dCyd and this phenotype is associated with an accumulation of abasic sites and DNA strand breaks in genomic DNA (11). It is therefore possible that some of these breaks are an indication of the formation of DNA repair intermediates induced by the presence of uracil and aza-uracil.…”

“…Additionally, the cytotoxic and mutagenic properties of decitabine may be partially derived from its intrinsic chemical instability once it is incorporated into DNA or by the accumulation of DNA repair intermediates (3). Recently, it has been proposed that the base excision repair mechanism (BER) might be initiating the repair of decitabine-induced DNA base lesions although the precise nature of the damage or the DNA glycosylases involved remains unknown (11).…”

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

“…CCC have been assumed to demonstrate an increased reliance on the HNF-1β-CHEK1 axis for cell survival (49). Significant genes involved in synthetic lethality with CHEK1 are reported to be ATR, MYC, TP53, WEE1 and CDKN1A (29,(61)(62)(63). ATR inhibition is currently assessed in early-phase clinical trials as single agents and in combination strategies, including PARP inhibitors (37).…”