Credit: Molecular Cell (2025). DOI: 10.1016/j.molcel.2025.11.009

A Northwestern Medicine study has revealed a previously unknown connection between two fundamental cellular processes, offering fresh insight into how human cells build and maintain chromatin, according to findings published in Molecular Cell.

For decades, scientists have known that the formation of chromatin—the complex of DNA and proteins in the cell’s nucleus that packs DNA strands into compact forms—depends on a steady supply of both nucleotides (the building blocks of DNA) and histones, the proteins around which DNA is tightly wrapped. But exactly how these two biosynthetic pathways stay synchronized has remained a mystery, said Dan Foltz, Ph.D., professor of Biochemistry and Molecular Genetics, who was senior author of the study.

"My lab has been interested in understanding chromatin and the proteins that are involved in building chromatin for some time," Foltz said. "In previous work, we had been surprised to find that proteins involved with chromatin had a connection to metabolism. Here, we explored that further."

Discovery of a missing molecular link

The new research identified a missing link: enzymes that initiate nucleotide synthesis also appear to play a direct, and unexpected, role in preparing histones for chromatin assembly.

In the current study, Foltz and his collaborators focused on phosphoribosyl pyrophosphate synthetases (PRPSs), enzymes best known for catalyzing the first step in making nucleotides. The scientists found the loss of PRPS1 or PRPSAP1 severely disrupted histone maturation.

The findings suggest that PRPS enzymes play an additional, previously unknown role: helping regulate early steps in histone maturation, independent of their metabolic duties.

This dual function effectively synchronizes two vital systems—nucleotide biosynthesis and histone production—ensuring that DNA replication and chromatin assembly proceed smoothly and at matching speeds.

Implications for genome stability and disease

"For the longest time, DNA synthesis and histone deposition were thought to occur independently," said Shashank Srivastava, Ph.D., research assistant professor of Biochemistry and Molecular Genetics, who was first and co-corresponding author of the study. "These enzymes have evolved in such a way that, on one hand, they’re regulating the DNA synthesis by providing the nucleotides. And at the same time, they’re also engaging with several other proteins, which we know as histone chaperones, that assist in the deposition of the newly synthesized histones on the DNA to complete the assembly of chromatin."

Chromatin assembly is essential for safeguarding genome integrity, Srivastava said. When histones are scarce or improperly processed, cells face an increased risk of DNA damage and replication stress, conditions linked to cancer, aging and other diseases.

By identifying PRPS enzymes as coordinators of nucleotide and histone supply, the study opens new avenues for exploring metabolic influences on genome maintenance, according to the authors. It may also provide a deeper understanding of disorders involving PRPS mutations, which have been associated with cancer, neurological diseases and metabolic syndromes.

Broader significance and future directions

In revealing this connection, Foltz and his collaborators also highlight a broader principle: that cellular biosynthetic pathways may be far more intertwined than previously thought.

"In the context of DNA replication and cell division, the findings show that two major biosynthetic pathways, which have to happen for you to copy your genome, are functionally linked," said Foltz, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "Any disruption in the process that would inhibit the deposition of histones on the DNA would leave DNA without histones, and that would increase the chances of DNA damage and genomic instability."

Taken together, the new findings detail a "previously unrecognized synchrony" between metabolism and chromatin regulation—offering a significant step forward in understanding how human cells balance the complex demands of DNA replication, gene expression and growth.

"We employed a robust degron system, which enables the rapid depletion of PRPS proteins. This is the first study using the degron approach for PRPS enzyme complex components. This approach allowed us to disambiguate their established role in nucleotide biosynthesis from their role in histone deposition. Our results demonstrate that histone deposition is acutely sensitive to PRPS complex function and occurs independently of any detectable DNA replication defects," Srivastava said.

"Both nucleotide metabolism and chromatin assembly are dysregulated in diseases, including B-cell leukemia and neurological disorders. Going forward, we aim to test whether disruption in this newly identified link contributes to disease. No one has really thought about these proteins having additional functions in histone deposition."

More information: Shashank Srivastava et al, Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation, Molecular Cell (2025). DOI: 10.1016/j.molcel.2025.11.009

Citation: Understanding the link between nucleotide metabolism and chromatin assembly (2026, January 8) retrieved 8 January 2026 from https://phys.org/news/2026-01-link-nucleotide-metabolism-chromatin.html

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