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Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.

Alterations in deoxyribonucleoside triphosphate (dNTP) pools have been linked to increased mutation rates and genome instability in unicellular organisms and cell cultures. However, the role of dNTP pool changes in tumor development in mammals remains unclear. In this study, we present a mouse model with a point mutation at the allosteric specificity site of ribonucleotide reductase, RRM1-Y285A. This mutation reduced ribonucleotide reductase activity, impairing the synthesis of deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP). Heterozygous Rrm1^+/Y285A mice exhibited distinct alterations in dNTP pools across various organs, shorter lifespans and earlier tumor onset compared with wild-type controls. Mutational spectrum analysis of tumors revealed two distinct signatures, one resembling a signature extracted from a human cancer harboring a mutation of the same amino acid residue in ribonucleotide reductase, RRM1^Y285C. Our findings suggest that mutations in enzymes involved in dNTP metabolism can serve as drivers of cancer development.

Endophytes either be bacteria, fungi, or actinomycetes colonize inside the tissue of host plants without showing any immediate negative effects on them. Among numerous natural alternative sources, fungal endophytes produce a wide range of structurally diverse bioactive metabolites including anticancer compounds. Considering the production of bioactive compounds in low quantity, genetic and physicochemical modification of the fungal endophytes is performed for the enhanced production of bioactive compounds. Presently, for the treatment of cancer, chemotherapy is majorly used, but the side effects of chemotherapy are of prime concern in clinical practices. Also, the drug-resistant properties of carcinoma cells, lack of cancer cells-specific medicine, and the side effects of drugs are the biggest obstacles in cancer treatment. The interminable requirement of potential drugs has encouraged researchers to seek alternatives to find novel bioactive compounds, and fungal endophytes seem to be a probable target for the discovery of anticancer drugs. The present review focuses a comprehensive literature on the major fungal endophyte-derived bioactive compounds which are presently been used for the management of cancer, biotic factors influencing the production of bioactive compounds and about the challenges in the field of fungal endophyte research.