OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug

Proceedings of the National Academy of Sciences of the United States of America
Shuvojit BanerjeeRobert H Silverman

Abstract

Drugs that reverse epigenetic silencing, such as the DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (AZA), have profound effects on transcription and tumor cell survival. AZA is an approved drug for myelodysplastic syndromes and acute myeloid leukemia, and is under investigation for different solid malignant tumors. AZA treatment generates self, double-stranded RNA (dsRNA), transcribed from hypomethylated repetitive elements. Self dsRNA accumulation in DNMTi-treated cells leads to type I IFN production and IFN-stimulated gene expression. Here we report that cell death in response to AZA treatment occurs through the 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway. OASs are IFN-induced enzymes that synthesize the RNase L activator 2-5A in response to dsRNA. Cells deficient in RNase L or OAS1 to 3 are highly resistant to AZA, as are wild-type cells treated with a small-molecule inhibitor of RNase L. A small-molecule inhibitor of c-Jun NH2-terminal kinases (JNKs) also antagonizes RNase L-dependent cell death in response to AZA, consistent with a role for JNK in RNase L-induced apoptosis. In contrast, the rates of AZA-induced and RNase L-dependent cell death were increased by transfection of 2-5A, by deficiencies in ADA...Continue Reading

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Sep 27, 2019·Nature Reviews. Drug Discovery·Claire Vanpouille-BoxLorenzo Galluzzi
Jan 31, 2020·Cellular and Molecular Life Sciences : CMLS·Taisuke Nakahama, Yukio Kawahara
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Mar 27, 2021·Frontiers in Oncology·Chryssoula KordellaIoannis Kotsianidis
Nov 14, 2021·Proceedings of the National Academy of Sciences of the United States of America·Alisha ChitrakarAlexei Korennykh

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Methods Mentioned

BETA
transfection
gene knockout

Software Mentioned

SAS
IncuCyte

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