Allosteric substrate activation of SAMHD1 shapes deoxynucleotide triphosphate imbalances by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 14, 2023

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism depends on dNTP binding at allosteric sites concomitant tetramerization enzyme. The study reveals involves an inactive tetrameric intermediate with partial occupancy sites. equilibrium between active states, which coupled to cooperative binding/dissociation least two ligands, controls activity enzyme, which, addition, identity dNTPs occupying four tetramer. We show how such regulation determines deoxynucleotide triphosphate levels established dynamic equilibria production SAMHD1-catalyzed depletion. Notably, enables distinctive functionality SAMHD1, call facilitated depletion, whereby elevated biosynthesis some results more efficient depletion others. regulatory relationship different sheds light emerging role biology homeostasis implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism SAMHD1, which involves dNTP binding at allosteric sites transient tetramerization. Our findings reveal tetramerization alone insufficient to promote hydrolysis; instead, requires an inactive tetrameric intermediate with partially occupied sites. The equilibrium between active states regulates activity, driven by dissociation additional ligands preassembled tetramer. Furthermore, catalytic efficiency, but not specificity, modulated identity dNTPs occupying We show how this regulation shapes deoxynucleotide homeostasis balancing production SAMHD1-catalyzed depletion. Notably, exhibits distinct functionality, term facilitated depletion, whereby increased biosynthesis certain enhances depletion others. regulatory relationship different sheds light on emerging role biology implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

Citations

3
CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond DOI Creative Commons
Jialin Lu,

Yuqing Ma,

Q. Quentin Li

et al.

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Aug. 23, 2024

Abstract With the advent of adoptive cellular therapy, chimeric antigen receptor (CAR)-T cell therapy has gained widespread application in cancer treatment and demonstrated significant efficacy against certain hematologic malignancies. However, due to limitations CAR-T treating solid tumors, other immune cells are being modified with CAR address this issue. Macrophages have emerged as a promising option, owing their extensive functions, which include presentation, powerful tumor phagocytosis, particularly active trafficking microenvironment. Leveraging unique advantages, CAR-macrophages (CAR-M) expected enhance effectiveness treatments novel form immunotherapy, potentially overcoming major challenges associated CAR-T/NK therapy. This review outlines primary mechanism underlying CAR-M recent progressions while also discussing further applications.

Language: Английский

Citations

14
Understanding the interplay between dNTP metabolism and genome stability in cancer DOI Creative Commons
Miriam Yagüe-Capilla, Sean G. Rudd

Disease Models & Mechanisms, Journal Year: 2024, Volume and Issue: 17(8)

Published: Aug. 1, 2024

ABSTRACT The size and composition of the intracellular DNA precursor pool is integral to maintenance genome stability, this relationship fundamental our understanding cancer. Key aspects carcinogenesis, including elevated mutation rates induction certain types damage in cancer cells, can be linked disturbances deoxynucleoside triphosphate (dNTP) pools. Furthermore, approaches treat heavily exploit metabolic interplay between dNTP pool, with a long-standing example being use antimetabolite-based therapies, strategy continues show promise development new targeted therapies. In Review, we compile current knowledge on both causes consequences perturbations together their impact stability. We outline several outstanding questions remaining field, such as role catabolism stability expansion. Importantly, detail how mechanistic these processes utilised aim providing better informed treatment options patients

Language: Английский

Citations

3
Metabolic constraint of human telomere length by nucleotide salvage efficiency DOI Creative Commons
William Mannherz, Andrew Crompton,

Noah Lampl

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 27, 2025

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based synthesis assay found that nucleoside salvage bidirectionally constrains human length. Metabolism of deoxyguanosine (dG) or guanosine via purine phosphorylase (PNP) hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase shortened telomeres. Conversely, dG its nucleotide forms deoxycytidine kinase drove potent activation, the extent which was controlled by dNTPase SAMHD1. Circumventing limits on expressing Drosophila melanogaster deoxynucleoside augmenting metabolism using PNP inhibitor ulodesine robustly lengthened telomeres in cells, including those from patients lethal diseases. Our results provide an updated paradigm for control, wherein reverse transcriptase activity actively constrained availability dNTP substrates, manner may be therapeutically actionable. Telomere normal cellular function population. authors reveal pools, manipulated.

Language: Английский

Citations

0
Allosteric substrate activation of SAMHD1 shapes deoxynucleotide triphosphate imbalances by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 14, 2023

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism depends on dNTP binding at allosteric sites concomitant tetramerization enzyme. The study reveals involves an inactive tetrameric intermediate with partial occupancy sites. equilibrium between active states, which coupled to cooperative binding/dissociation least two ligands, controls activity enzyme, which, addition, identity dNTPs occupying four tetramer. We show how such regulation determines deoxynucleotide triphosphate levels established dynamic equilibria production SAMHD1-catalyzed depletion. Notably, enables distinctive functionality SAMHD1, call facilitated depletion, whereby elevated biosynthesis some results more efficient depletion others. regulatory relationship different sheds light emerging role biology homeostasis implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

Citations

1