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Pyruvate kinase, a metabolic sensor powering glycolysis, drives the metabolic control of DNA replication

Horemans, Steff; Pitoulias, Matthaios; Holland, Alexandria; Pateau, Emilie; Lechaplais, Christophe; Ekaterina, Dariy; Perret, Alain; Soultanas, Panos; Janniere, Laurent


Steff Horemans

Matthaios Pitoulias

Alexandria Holland

Emilie Pateau

Christophe Lechaplais

Dariy Ekaterina

Alain Perret

Laurent Janniere


Background: In all living organisms,DNA replication is exquisitely regulated in a wide range of growth conditions to achieve timely and accurate genome duplication prior to cell division. Failures in this regulation cause DNA damage with potentially disastrous consequences for cell viability and human health,including cancer. To cope with these threats, cells tightlycontrol replication initiationusing well-known mechanisms. They alsocouple DNA synthesis to nutrient richness and growth ratethrough a poorly understood process thought to involve central carbon metabolism.One such processmay involve the cross-species conserved pyruvate kinase (PykA) which catalyzes the last reaction of glycolysis. Here we have investigated the role of PykA in regulating DNA replicationin the model system Bacillus subtilis. Results: On analysing mutants of the catalytic (Cat) and C-terminal (PEPut) domains of B. subtilis PykA we foundreplication phenotypes in conditions where PykA is dispensable for growth. These phenotypes are independent from the effect of mutations on PykA catalytic activity and are not associated with significant changes in the metabolome. PEPut operates as a nutrient-dependent inhibitor of initiation while Cat acts as a stimulator of replication fork speed. Disruption of either PEPut or Cat replication function dramatically impacted the cell cycle and replication timing even in cells fully proficient in known replication control functions. In vitro, PykA modulates activities of enzymes essential for replication initiation and elongation via functional interactions. Additional experiments showed that PEPut regulates PykA activity and that Cat and PEPut determinants important for PykA catalytic activity regulation are also important for PykA-driven replication functions. Conclusions: We infer from our findings that PykA typifies a new family of cross-species replication control regulators that drive the metabolic control of replication through a mechanism involving regulatory determinants of PykA catalytic activity. As disruption of PykA replication functions causes dramatic replication defects, we suggest that dysfunctions in this new family of universal replication regulators may pave the path to genetic instability and carcinogenesis.


Horemans, S., Pitoulias, M., Holland, A., Pateau, E., Lechaplais, C., Ekaterina, D., …Janniere, L. (2022). Pyruvate kinase, a metabolic sensor powering glycolysis, drives the metabolic control of DNA replication. BMC Biology, 20, Article 87.

Journal Article Type Article
Acceptance Date Feb 23, 2022
Online Publication Date Apr 13, 2022
Publication Date Dec 1, 2022
Deposit Date Feb 25, 2022
Publicly Available Date Apr 13, 2022
Journal BMC Biology
Electronic ISSN 1741-7007
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 20
Article Number 87
Keywords Cell Biology; Developmental Biology; Plant Science; General Agricultural and Biological Sciences; General Biochemistry, Genetics and Molecular Biology; Physiology; Ecology, Evolution, Behavior and Systematics; Structural Biology; Biotechnology
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