CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity

TL;DR

CDADC1 is a vertebrate enzyme that converts dCTP to dUTP and inactivates cancer drugs, affecting their efficacy and toxicity.

Contribution

CDADC1 is identified as a vertebrate-specific dCTP deaminase with a role in drug metabolism and toxicity.

Findings

CDADC1 converts dCTP to dUTP but is not essential for mammalian cell proliferation or mouse viability.

CDADC1 inactivates gemcitabine and decitabine, reducing their efficacy in cancer cells.

CDADC1 deficiency increases drug efficacy but also causes hypersensitivity to gemcitabine in mice.

Abstract

We identify CDADC1, an orphan enzyme unique to vertebrates, as a dCTP deaminase that produces dUTP. This reaction was previously reported only in some bacteria, where it supports de novo synthesis of dTTP. However, we rule out a main role of CDADC1 in dTTP biosynthesis, cell proliferation, or mouse viability. Nonetheless, CDADC1’s activity implies a role for dUTP in vertebrate cells, challenging the prevailing view of dUTP solely as a toxic byproduct. In addition, CDADC1 metabolizes and inactivates the nucleotide analogs gemcitabine and decitabine. CDADC1 deficiency in cancer cells increases these drugs’ efficacy but also protects mice from lethal gemcitabine-induced toxicity. We reveal a biochemical pathway in vertebrate nucleotide metabolism with clinical implications for optimizing gemcitabine and decitabine treatment.

Cancer therapy is limited by resistance to standard-of-care chemotherapeutic and/or by treatment-associated toxicity. Identifying molecular mechanisms that modulate cellular toxicity is crucial for enhancing treatment efficacy. We characterize CDADC1, a vertebrate-specific orphan enzyme, as an unprecedented eukaryotic dCTP deaminase. CDADC1 catalyzes the conversion of dCTP into dUTP. While bacteria use this activity to sustain proliferation, CDADC1 evolved independently and is not required for mammalian cell proliferation, as demonstrated in cell lines and by the normal growth and standard lifespan of Cdadc1-deficient mice. However, we uncover a role of CDADC1 in metabolizing nucleotide analogs gemcitabine and decitabine. Gain- and loss-of-function assays in cancer cell lines, along with ectopic mouse models of pancreatic cancer, show that CDADC1 reduces these drugs’ efficacy. By the same token, Cdadc1−/− mice are hypersensitive to gemcitabine. Mechanistically, CDADC1 deaminates the active triphosphate form of gemcitabine and decitabine, rendering them susceptible to inactivation by deoxyuridine triphosphatase. In contrast, the dCMP deaminase DCTD contributes to cell proliferation and promotes gemcitabine and decitabine toxicity. Thus, CDADC1 underpins a previously unrecognized mechanism of intrinsic chemoresistance in cancer cells and has a nonredundant role in protecting from gemcitabine toxicity. CDADC1 reveals a clinically relevant metabolic pathway that might be exploited to enhance the efficacy of deoxycytidine analogs but calls for assessing CDADC1 status to avoid lethal toxicities.

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