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Proteogenomic Study Expands Catalog of Cell Cycle Players

NEW YORK – Investigators in Sweden, the US, and the UK have identified hundreds of new cell cycle proteins using a single-cell proteogenomic strategy — a collection they incorporated into the Human Protein Atlas to bolster future studies of cell cycle regulation, progression, proliferation, and related processes.

"The cell cycle, over which cells grow and divide, is a fundamental process of life," senior author Emma Lundberg, a researcher at the Science for Life Laboratory in Sweden and a professor at the KTH Royal Institute of Technology, and her colleagues explained in their Nature paper on Wednesday, noting that cell cycle dysregulation "has devastating consequences, including cancer."

Using single-cell RNA sequencing on more than 1,150 cells isolated by fluorescence-activated cell sorting (FACS) — together with targeted single-cell proteomic imaging, immunofluorescent imaging, protein tagging, and other approaches — the researchers attempted to tease out new and known cycling proteins and cell-to-cell protein variability in time and space in human cells tagged with a fluorescent ubiquitination-based cell cycle indicator system for visualizing cell cycle progression. 

"We believe this mosaic will serve as a valuable resource to facilitate a greater functional understanding of the orchestration and stochasticity of cell-to-cell variability, the human cell cycle, the roles of newly identified cycling proteins in tumorigenesis, and the potential application of these proteins as new clinical markers for cellular proliferation," the authors wrote.

In the process, they uncovered hundreds of proteins with previously unappreciated roles in mitosis or other cell cycle-related processes, including established or suspected oncogenes.

In particular, the team highlighted 320 proteins with temporal ties to progression through interphase of the cell cycle. Moreover, the results suggested cell cycle-dependent proteins appear to be largely regulated through translational or post-translational processes rather than through cycling transcription or gene expression.

"This is remarkable given how well studied the cell cycle is," Lundberg said in an email, noting that "most of the novel cell cycle proteins show cyclic expression patterns at the protein level, while being stably expressed at the RNA level."

The team also detected nearly 2,200 proteins showing variability from one cell to the next. Proteins with distinct patterns between cells that did not exhibit cell cycle-related variability tended to be modified by metabolism-regulating kinase enzymes, the authors noted, while cell cycle progression-related proteins appeared more prone to phosphorylation by cell fate-related kinase enzymes.

These and other findings gleaned from the study "provide a more complete picture of the cell division cycle and proteomic variability between individual human cells," they wrote, "which is crucial for understanding the molecular underpinnings of these fundamental biological processes and emergent proliferative diseases."

Lundberg noted that the investigators are now focused on follow-up studies looking more closely at the newly recognized cell cycle-related proteins and their potential use as proliferation markers, along with analyses centered on the transition from cell proliferation to cellular quiescence.