Abstract
Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. Herein, we find that the anaphase-promoting complex/cyclosome (APC/C) synchronizes ribose-5-phosphate levels and DNA synthesis during the cell cycle. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1-transketolase heterodimers that accumulate ribose-5-phosphate. This accumulation occurs by asymmetric production of ribose-5-phosphate from the non-oxidative pentose phosphate pathway and prevention of ribose-5-phosphate removal by depleting transketolase homodimers. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. TKTL1-overexpressing cancer cells exhibit elevated ribose-5-phosphate levels. The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. Here we reveal that the cell cycle control machinery regulates DNA synthesis by mediating ribose-5-phosphate sufficiency.
Highlights
Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication
The Pulled-In theory is supported by several observations, including that PRPP-producing pyrophosphokinase (PRPS)[13] is activated in rapidly-growing cells[17,18] and that the concentration of nucleotides increases from late G1 to S phase and decreases after completion of DNA duplication[19], this model does not explain whether and how R5P sufficiency in phosphate pathway (PPP) is attained from late G1 to S phase
After double thymidinesynchronized G1/S phase HeLa cells were released, transketolase-like 1 (TKTL1) protein levels remained elevated during S phase, decreased when cells progressed into G2/M phase, and bounced back after cells reentered G1 phase (Fig. 1b and Supplementary Fig. 1a; 0–11h)
Summary
Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1transketolase heterodimers that accumulate ribose-5-phosphate. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. The low CDH1 or high TKTL1-induced accumulation of ribose-5phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. The Pulled-In theory is supported by several observations, including that PRPP-producing pyrophosphokinase (PRPS)[13] is activated in rapidly-growing cells[17,18] and that the concentration of nucleotides increases from late G1 to S phase and decreases after completion of DNA duplication[19], this model does not explain whether and how R5P sufficiency in PPP is attained from late G1 to S phase. The bidirectional activities of TKT make it a possible key R5Pregulating enzyme that determines R5P levels by changing catalytic directions and altering substrate specificities
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