Journal Article

CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer

Kessler, Benedikt M., Zauri, Melania, Pugh, Kathryn M., Thézénas, Marie-Laëtitia, Berridge, Georgina, Goldin, Robert, Kriaucionis, Skirmantas

2015

Overview

Enzymes of the nucleotide salvage pathway are shown to have substrate selectivity that protects newly synthesized DNA from random incorporation of epigenetically modified forms of cytosine; a subset of cancer cell lines that overexpress cytidine deaminase (CDA) are sensitive to treatment with 5hmdC or 5fdC (oxidized forms of 5-methyl-cytosine), which leads to DNA damage and cell death, indicating the chemotherapeutic potential of these nucleoside variants for CDA-overexpressing cancers. Specificity in nucleotide recycling As well as synthesizing DNA nucleotides de novo , cells utilize nucleotides recycled from dying cells. It is unclear how the nucleotide salvage pathway deals with the various oxidized forms of 5-methyl-cytosine such as 5hmdC and 5fdC. Here Skirmantas Kriaucionis and colleagues demonstrate that the nucleotide salvage pathway has a substrate selectivity that protects newly synthesized DNA from random incorporation of epigenetically modified forms of cytosine. However, some cancer cells that overexpress cytidine deaminase (CDA) are sensitive to overexpression of 5hmdC or 5fdC, which leads to DNA damage and cell death. The authors speculate that drugs based on these nucleoside variants may have chemotherapeutic potential in CDA-overexpressing cancers. Cells require nucleotides to support DNA replication and repair damaged DNA. In addition to de novo synthesis, cells recycle nucleotides from the DNA of dying cells or from cellular material ingested through the diet. Salvaged nucleosides come with the complication that they can contain epigenetic modifications. Because epigenetic inheritance of DNA methylation mainly relies on copying of the modification pattern from parental strands 1 , 2 , 3 , random incorporation of pre-modified bases during replication could have profound implications for epigenome fidelity and yield adverse cellular phenotypes. Although the salvage mechanism of 5-methyl-2′deoxycytidine (5mdC) has been investigated before 4 , 5 , 6 , it remains unknown how cells deal with the recently identified oxidized forms of 5mdC: 5-hydroxymethyl-2′deoxycytidine (5hmdC), 5-formy-2′deoxycytidine (5fdC) and 5-carboxyl-2′deoxycytidine (5cadC) 7 , 8 , 9 , 10 . Here we show that enzymes of the nucleotide salvage pathway display substrate selectivity, effectively protecting newly synthesized DNA from the incorporation of epigenetically modified forms of cytosine. Thus, cell lines and animals can tolerate high doses of these modified cytidines without any deleterious effects on physiology. Notably, by screening cancer cell lines for growth defects after exposure to 5hmdC, we unexpectedly identify a subset of cell lines in which 5hmdC or 5fdC administration leads to cell lethality. Using genomic approaches, we show that the susceptible cell lines overexpress cytidine deaminase (CDA). CDA converts 5hmdC and 5fdC into variants of uridine that are incorporated into DNA, resulting in accumulation of DNA damage, and ultimately, cell death. Our observations extend current knowledge of the nucleotide salvage pathway by revealing the metabolism of oxidized epigenetic bases, and suggest a new therapeutic option for cancers, such as pancreatic cancer, that have CDA overexpression and are resistant to treatment with other cytidine analogues 11 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/51 / 38/22 / 38/61 / 5-Methylcytosine - metabolism / 5-Methylcytosine - pharmacology / 631/337/1644 / 631/337/176/1988 / 631/45/147 / 631/67 / 64/60 / 82/16 / 82/58 / 82/80 / 82/83 / Animals / Cancer / Care and treatment / Cell Death - drug effects / Cell Line, Tumor / Cytidine - analogs & derivatives / Cytidine - chemistry / Cytidine - metabolism / Cytidine - pharmacology / Cytidine Deaminase - genetics / Cytidine Deaminase - metabolism / Cytosine - analogs & derivatives / Cytosine - chemistry / Cytosine - metabolism / Cytosine - pharmacology / Cytotoxicity / Deoxycytidine - analogs & derivatives / Deoxycytidine - metabolism / Deoxycytidine - pharmacology / Deoxyribonucleic acid / DNA / DNA - biosynthesis / DNA - chemistry / DNA Damage - drug effects / DNA polymerase / DNA-Directed DNA Polymerase - metabolism / Enzymes / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Gene expression / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Kinases / letter / Metabolism / Mice / multidisciplinary / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - metabolism / Nucleosides / Nucleotides - chemistry / Nucleotides - metabolism / Nucleotides - pharmacology / Oxidation-Reduction / Pancreatic cancer / Phosphotransferases - metabolism / Science / Substrate Specificity / Up-Regulation / Uridine - analogs & derivatives / Uridine - chemistry / Uridine - metabolism