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

Kohnken R, Kodigepalli KM, Wu L - Mol. Cancer (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH, 43210, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Dysregulation of dNTPs in cancer pathogenesis and its targeted therapy. Nucleotides are derived from multiple intracellular sources, including products of glycolysis, folate cycle, and scavenging of degraded components. The reduction of dihydrofolate to active tetrahydrofolate is inhibited by the chemotherapeutic methotrexate. Pyrimidine and purine bases are both reduced to deoxynucleosides (dN) by ribonucleotide reductase (RNR). This reaction is inhibited by the chemotherapeutic hydroxyurea. Other steps in this reaction are inhibited by numerous nucleoside analogs (“antimetabolite” compounds) including 5-fluorouracil. These drugs function by limiting the deoxynucleoside triphosphate (dNTP) pool available for DNA synthesis and triggering the S-phase checkpoint via the action of ATR and Chk1, resulting in cell cycle arrest by inhibiting the activation of cyclin dependent kinase 1 (CDK1). A potentially critical regulator of this pathway is SAMHD1, which hydrolyses dNTPs into products that are then recycled or degraded. By this action, SAMHD1 limits dNTP pool in G1 phase and prevents DNA replication. With loss of function or repression of SAMHD1 expression, the dNTP pool is not reduced which can result in DNA damage and inappropriate cell cycle progression. DHFR, dihydrofolate reductase; PPPs, triphosphate; ATR, ataxia-telangiectasia and Rad3-related protein; Cdc25, cell division cycle 25
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Fig1: Dysregulation of dNTPs in cancer pathogenesis and its targeted therapy. Nucleotides are derived from multiple intracellular sources, including products of glycolysis, folate cycle, and scavenging of degraded components. The reduction of dihydrofolate to active tetrahydrofolate is inhibited by the chemotherapeutic methotrexate. Pyrimidine and purine bases are both reduced to deoxynucleosides (dN) by ribonucleotide reductase (RNR). This reaction is inhibited by the chemotherapeutic hydroxyurea. Other steps in this reaction are inhibited by numerous nucleoside analogs (“antimetabolite” compounds) including 5-fluorouracil. These drugs function by limiting the deoxynucleoside triphosphate (dNTP) pool available for DNA synthesis and triggering the S-phase checkpoint via the action of ATR and Chk1, resulting in cell cycle arrest by inhibiting the activation of cyclin dependent kinase 1 (CDK1). A potentially critical regulator of this pathway is SAMHD1, which hydrolyses dNTPs into products that are then recycled or degraded. By this action, SAMHD1 limits dNTP pool in G1 phase and prevents DNA replication. With loss of function or repression of SAMHD1 expression, the dNTP pool is not reduced which can result in DNA damage and inappropriate cell cycle progression. DHFR, dihydrofolate reductase; PPPs, triphosphate; ATR, ataxia-telangiectasia and Rad3-related protein; Cdc25, cell division cycle 25

Mentions: Given the important role of nucleotide metabolism in cell proliferation, transformation and tumor progression, inhibition of nucleotide synthesis has been commonly used in treatment of cancer, as well as infectious and immune-mediated diseases [3]. Inhibiting DNA precursor synthesis or incorporation of nucleoside analogs into DNA results in DNA damage and stalled replication forks, followed by activation of the S-phase checkpoint, which may lead to cell death by apoptosis [3] (Fig. 1). Methotrexate and similar compounds that inhibit dihydrofolate reductase required for purine biosynthesis [34], are widely used in chemotherapy for solid and lymphocytic tumors. On the other hand, purine and pyrimidine analogs such as forodesine and gemcitabine respectively, can disrupt DNA replication [35]. Moreover, 5-fluorouracil is a pyrimidine adduct that is misincorporated into DNA and inhibits nucleotide synthesis [34]. Most of clinically available nucleoside analogs act by incorporation into DNA, which relies on balanced dNTP pool for high fidelity of incorporation during replication. Excess intracellular dNTPs may out-compete these nucleoside analogs, thus conferring chemotherapeutic resistance [36]. For this reason, these drugs may be used in combination with other therapies, such as inhibitors of RNR that reduce dNTP pool. Efficient RNR inhibition is accomplished by hydroxyurea, a free radical scavenger and iron chelator that inactivates the catalytic capacity of the R2 subunit of RNR [3]. Current clinically used inhibitors of RNR, such as hydroxyurea or gemcitabine, have limitations, including severe cytotoxicity, short half-life, and drug resistance when used as a single therapy. New horizons for nucleotide synthesis-directed therapy include small molecule targeting subunit activity modulation, such as anti-sense oligonucleotides and gene therapy targeting RNR [3, 26].Fig. 1


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

Kohnken R, Kodigepalli KM, Wu L - Mol. Cancer (2015)

Dysregulation of dNTPs in cancer pathogenesis and its targeted therapy. Nucleotides are derived from multiple intracellular sources, including products of glycolysis, folate cycle, and scavenging of degraded components. The reduction of dihydrofolate to active tetrahydrofolate is inhibited by the chemotherapeutic methotrexate. Pyrimidine and purine bases are both reduced to deoxynucleosides (dN) by ribonucleotide reductase (RNR). This reaction is inhibited by the chemotherapeutic hydroxyurea. Other steps in this reaction are inhibited by numerous nucleoside analogs (“antimetabolite” compounds) including 5-fluorouracil. These drugs function by limiting the deoxynucleoside triphosphate (dNTP) pool available for DNA synthesis and triggering the S-phase checkpoint via the action of ATR and Chk1, resulting in cell cycle arrest by inhibiting the activation of cyclin dependent kinase 1 (CDK1). A potentially critical regulator of this pathway is SAMHD1, which hydrolyses dNTPs into products that are then recycled or degraded. By this action, SAMHD1 limits dNTP pool in G1 phase and prevents DNA replication. With loss of function or repression of SAMHD1 expression, the dNTP pool is not reduced which can result in DNA damage and inappropriate cell cycle progression. DHFR, dihydrofolate reductase; PPPs, triphosphate; ATR, ataxia-telangiectasia and Rad3-related protein; Cdc25, cell division cycle 25
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587406&req=5

Fig1: Dysregulation of dNTPs in cancer pathogenesis and its targeted therapy. Nucleotides are derived from multiple intracellular sources, including products of glycolysis, folate cycle, and scavenging of degraded components. The reduction of dihydrofolate to active tetrahydrofolate is inhibited by the chemotherapeutic methotrexate. Pyrimidine and purine bases are both reduced to deoxynucleosides (dN) by ribonucleotide reductase (RNR). This reaction is inhibited by the chemotherapeutic hydroxyurea. Other steps in this reaction are inhibited by numerous nucleoside analogs (“antimetabolite” compounds) including 5-fluorouracil. These drugs function by limiting the deoxynucleoside triphosphate (dNTP) pool available for DNA synthesis and triggering the S-phase checkpoint via the action of ATR and Chk1, resulting in cell cycle arrest by inhibiting the activation of cyclin dependent kinase 1 (CDK1). A potentially critical regulator of this pathway is SAMHD1, which hydrolyses dNTPs into products that are then recycled or degraded. By this action, SAMHD1 limits dNTP pool in G1 phase and prevents DNA replication. With loss of function or repression of SAMHD1 expression, the dNTP pool is not reduced which can result in DNA damage and inappropriate cell cycle progression. DHFR, dihydrofolate reductase; PPPs, triphosphate; ATR, ataxia-telangiectasia and Rad3-related protein; Cdc25, cell division cycle 25
Mentions: Given the important role of nucleotide metabolism in cell proliferation, transformation and tumor progression, inhibition of nucleotide synthesis has been commonly used in treatment of cancer, as well as infectious and immune-mediated diseases [3]. Inhibiting DNA precursor synthesis or incorporation of nucleoside analogs into DNA results in DNA damage and stalled replication forks, followed by activation of the S-phase checkpoint, which may lead to cell death by apoptosis [3] (Fig. 1). Methotrexate and similar compounds that inhibit dihydrofolate reductase required for purine biosynthesis [34], are widely used in chemotherapy for solid and lymphocytic tumors. On the other hand, purine and pyrimidine analogs such as forodesine and gemcitabine respectively, can disrupt DNA replication [35]. Moreover, 5-fluorouracil is a pyrimidine adduct that is misincorporated into DNA and inhibits nucleotide synthesis [34]. Most of clinically available nucleoside analogs act by incorporation into DNA, which relies on balanced dNTP pool for high fidelity of incorporation during replication. Excess intracellular dNTPs may out-compete these nucleoside analogs, thus conferring chemotherapeutic resistance [36]. For this reason, these drugs may be used in combination with other therapies, such as inhibitors of RNR that reduce dNTP pool. Efficient RNR inhibition is accomplished by hydroxyurea, a free radical scavenger and iron chelator that inactivates the catalytic capacity of the R2 subunit of RNR [3]. Current clinically used inhibitors of RNR, such as hydroxyurea or gemcitabine, have limitations, including severe cytotoxicity, short half-life, and drug resistance when used as a single therapy. New horizons for nucleotide synthesis-directed therapy include small molecule targeting subunit activity modulation, such as anti-sense oligonucleotides and gene therapy targeting RNR [3, 26].Fig. 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, 1900 Coffey Road, Columbus, OH, 43210, USA.

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.

No MeSH data available.


Related in: MedlinePlus