| RCC1 (regulator of chromosome condensation 1) is the canonical guanine nucleotide exchange factor for the Ran GTPase and a chromatin-bound scaffold that establishes the RanGTP gradient across the nuclear envelope and on mitotic chromosomes, thereby coordinating nucleocytoplasmic transport, nuclear envelope dynamics, and spindle assembly with cell‑cycle progression. The protein adopts a seven‑bladed β‑propeller fold that binds directly to nucleosomes and double‑stranded DNA, and this chromatin association concentrates RCC1–Ran complexes on chromosomes so that GDP–GTP exchange on Ran generates high local RanGTP, while RanGAP and RanBP1 in the cytoplasm promote RanGDP, together forming a spatially polarized Ran system that governs cargo release from importins in the nucleus and promotes assembly of spindle and nuclear envelope components in the vicinity of chromatin. During interphase, RCC1‑driven nuclear RanGTP maintains directionality of classical importin‑β–dependent protein import and exportin‑mediated RNA and protein export, and perturbation of RCC1 levels or activity disrupts this transport, leading to mislocalization of key regulators and defects in G1/S transition and mitotic entry. During mitosis, high chromosome-associated RanGTP generated by RCC1 activates spindle assembly factors such as TPX2 and NuMA by liberating them from importin complexes, promotes proper kinetochore–microtubule attachments, and supports timely metaphase–anaphase transition; RCC1 also contributes to inner centromere composition and kinetochore regulation in ways that include Ran‑independent displacement of Shugoshin‑1 and the chromosomal passenger complex at the metaphase–anaphase transition. RCC1 is frequently overexpressed and behaves as a tumor facilitator: integrative pan‑cancer analyses show that high RCC1 levels correlate with cell‑cycle gene signatures, increased proliferation indices, immunosuppressive tumor microenvironment features, and poor prognosis, and functional studies in clear cell renal cell carcinoma demonstrate that RCC1 supports G1/S progression, suppresses apoptosis, and stabilizes EZH2 protein, so that RCC1 knockdown reduces proliferation, increases apoptotic markers, and promotes EZH2 degradation. Targeted RCC1 silencing in breast and lung cancer models similarly reduces viability, colony formation, and migration, increases apoptosis, and downregulates pathways involved in DNA replication and repair, highlighting a broader role for RCC1 in sustaining oncogenic survival and cell‑cycle programs. RCC1 also acts as an oncogenic driver that maintains cytoplasmic Skp2 and low p27Kip1 levels; loss of RCC1 disrupts Skp2 nucleo‑cytoplasmic trafficking and stability, leading to p27 accumulation and G1 arrest, which further links RCC1’s Ran‑dependent transport function to control of ubiquitin ligase activity and CDK regulation in tumor cells. In the nervous system, newly described biallelic RCC1 missense variants cause an autosomal-recessive acute-onset axonal neuropathy in children, where mutant RCC1 proteins show reduced GDP–GTP exchange activity and decreased thermal stability, and patient fibroblasts exhibit stress‑induced defects in Ran nuclear localization and nucleocytoplasmic transport, indicating that intact RCC1–Ran signaling is required for axonal integrity and that RCC1 dysfunction can underlie severe, infection‑triggered neurodegeneration that clinically mimics Guillain–Barré syndrome. |
