title: 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.
authors: Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes 6, 41012 Seville, Spain Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden.
authors: Manuel Luis
authors: ML
authors: Orta
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden.
authors: Andreas
authors: A
authors: Höglund
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden Department of Pharmacology, Faculty of Pharmacy, University of Seville, c/Professor García González, No. 2, 41012 Seville, Spain.
authors: José Manuel
authors: JM
authors: Calderón-Montaño
authors: Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes 6, 41012 Seville, Spain.
authors: Inmaculada
authors: I
authors: Domínguez
authors: Department of Pharmacology, Faculty of Pharmacy, University of Seville, c/Professor García González, No. 2, 41012 Seville, Spain.
authors: Estefanía
authors: E
authors: Burgos-Morón
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden.
authors: Torkild
authors: T
authors: Visnes
authors: Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes 6, 41012 Seville, Spain.
authors: Nuria
authors: N
authors: Pastor
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden.
authors: Cecilia
authors: C
authors: Ström
authors: Department of Pharmacology, Faculty of Pharmacy, University of Seville, c/Professor García González, No. 2, 41012 Seville, Spain.
authors: Miguel
authors: M
authors: López-lázaro
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden thomas.helleday@scilifelab.se.
authors: Thomas
authors: T
authors: Helleday
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000633:toxicity; D045744:Cell Line, Tumor; D006224:Cricetinae; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis; D018736:DNA Adducts / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000032:analysis; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059767:Recombinational DNA Repair; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000964:Antimetabolites, Antineoplastic; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine; C531550:olaparib