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.
Highlights
Decitabine (5-aza-2 -deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML)
5-aza-2 -deoxycytidine (5-azadC) and 5-azacytidine (5azaC) are synthetic cytidine analogues highly effective in the treatment of myelodysplastic syndromes (MDS), with 5-azadC showing good clinical response in older patients diagnosed with acute myeloid leukemia (AML) [1,2,3]. 5-azaC and 5-azadC were synthesized in the 60s as conventional cytostatic drugs [4] but were later discovered to demethylate DNA through their interactions with DNA methyltransferases (DNMTs) [5]
Chromosomal aberrations were analyzed in X-ray repair cross-complementing protein 1 (XRCC1) deficient EM9 and parental AA8 cells treated with 5-azadC after a 12-h repair period
Summary
Decitabine (5-aza-2 -deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). 5-azadC-induced DNMT foci persist in XRCC1 defective cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. 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 5azadC to improve treatment of MDS and AML. 5-aza-2 -deoxycytidine (5-azadC) and 5-azacytidine (5azaC) are synthetic cytidine analogues highly effective in the treatment of myelodysplastic syndromes (MDS), with 5-azadC showing good clinical response in older patients diagnosed with acute myeloid leukemia (AML) [1,2,3]. XRCC1 deficient mice are embryonic lethal [11] and XRCC1 deficient cells display increased levels of spontaneous ␥ -H2AX and RAD51 foci [12], and are hypersensitive to agents that induce SSBs or base damage [13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
