CYCLON is a nucleolar protein that regulates pan-cancer cell fitness through ribosome biogenesis

Abstract

Tumor progression is driven by cancer cell fitness, defined as the capacity of malignant cells to maintain growth, adapt to stress and withstand therapy Cellular fitness is fundamentally governed by nucleolar processes, which act as central regulators by integrating RNA processing with ribosome biogenesis to support protein synthesis and stress adaptation. The nuclear protein CYCLON, containing a large intrinsically disordered region (IDR) could be implicated in mediating biomolecular condensates and regulatory plasticity, which are key elements of nucleolar biology. CYCLON also emerged as a candidate regulator of cancer cell fitness, as it is frequently overexpressed across tumor types. Inducible silencing and cell biology approaches have shown that CYCLON maintains nucleolar integrity, controls nucleoli size and number, nucleolin and Ki-67 distribution and prevents nucleolar stress. CYCLON contributes to ribosome biogenesis by binding ribosomal RNA (rRNA) and regulating 32S and 21S pre-rRNA processing, ultimately influencing ribosomal subunit production and global protein synthesis. Its depletion impairs proliferation and clonogenic capacity by prolonging both interphase and mitosis, leading to slowed cell cycle progression. The impact of CYCLON on cellular fitness has been consistently observed across cancer models, reinforcing its essential role in the regulation of nucleolar biology.