Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications.

Rebecca Kohnken,Li Wu,Karthik M Kodigepalli

doi:10.1186/s12943-015-0446-6

Abstract

Regulation of intracellular deoxynucleoside triphosphate (dNTP) pool is critical to genomic stability and cancer development. Imbalanced dNTP pools can lead to enhanced mutagenesis and cell proliferation resulting in cancer development. Therapeutic agents that target dNTP synthesis and metabolism are commonly used in treatment of several types of cancer. Despite several studies, the molecular mechanisms that regulate the intracellular dNTP levels and maintain their homeostasis are not completely understood. The discovery of SAMHD1 as the first mammalian dNTP triphosphohydrolase provided new insight into the mechanisms of dNTP regulation. SAMHD1 maintains the homeostatic dNTP levels that regulate DNA replication and damage repair. Recent progress indicates that gene mutations and epigenetic mechanisms lead to downregulation of SAMHD1 activity or expression in multiple cancers. Impaired SAMHD1 function can cause increased dNTP pool resulting in genomic instability and cell-cycle progression, thereby facilitating cancer cell proliferation. This review summarizes the latest advances in understanding the importance of dNTP metabolism in cancer development and the novel function of SAMHD1 in regulating this process.

Highlights

Balanced levels of intracellular deoxynucleoside triphosphate (dNTP), the building blocks of DNA, are critical in maintaining the genomic integrity of cells
While a reduction or imbalance in dNTPs is known to result in genotoxicity and increased mutagenesis, an increase in dNTPs often results in uncontrolled DNA replication with reduced fidelity that can contribute to cancer development [1, 2]
Mutagenesis and disruption of genomic stability are two important factors leading to cancer development, which can be prevented by maintenance of optimal intracellular dNTP pools

Summary

Introduction

Balanced levels of intracellular dNTPs, the building blocks of DNA, are critical in maintaining the genomic integrity of cells. This biphasic regulation is critical to supply dNTPs for DNA synthesis, and to prevent excess intracellular dNTPs in the absence of DNA replication, which can contribute to innate immune activation [25] and cancer development [22]. Recent progress in literature suggests that RNR-mediated increase in dNTP pools is accompanied by higher mutation rates due to reduced fidelity of DNA replication or activation of translesion synthesis [26].

Results

Conclusion