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Nucleotide imbalance decouples cell growth from cell proliferation.

ABSTRACT: Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication and impeding DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways like mTORC1, Akt and AMPK signalling cascades, causing excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signalling to survive during, and recover from, nucleotide imbalance during S phase. We find that ATR-dependent replication stress signalling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signalling to cope with this metabolic problem and disrupting the coordination of cell growth and division.

SUBMITTER: Diehl FF

PROVIDER: S-EPMC9359916 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Nucleotide imbalance decouples cell growth from cell proliferation.

Diehl Frances F FF Miettinen Teemu P TP Elbashir Ryan R Nabel Christopher S CS Darnell Alicia M AM Do Brian T BT Manalis Scott R SR Lewis Caroline A CA Vander Heiden Matthew G MG

Nature cell biology 20220804 8

Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is not well understood. Here we find that e ...[more]

PMID: 35927450

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Dataset Information

Nucleotide imbalance decouples cell growth from cell proliferation.

Publications

Nucleotide imbalance decouples cell growth from cell proliferation.

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