title: Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications.
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.
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH, 43210, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kohnken
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH, 43210, USA.
authors.forename: Karthik M
authors.initials: KM
authors.lastname: Kodigepalli
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH, 43210, USA. wu.840@osu.edu.|Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA. wu.840@osu.edu.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. wu.840@osu.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D049109:Cell Proliferation; D004261:DNA Replication / Q000235:genetics; D003854:Deoxyribonucleotides / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D003854:Deoxyribonucleotides; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins