Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Abstract

The S-phase Kinase-Associated Protein 1 (SKP1) is a core component of the SKP1, Cullin 1, F-box protein (SCF) complex, an E3 ubiquitin ligase that serves to poly-ubiquitinate a vast array of protein targets as a signal for their proteasomal degradation, thereby playing a critical role in the regulation of downstream biological processes. Many of the proteins regulated by SKP1 and the SCF complex normally function within pathways that are essential for maintaining genome stability, including DNA damage repair, apoptotic signaling, and centrosome dynamics. Accordingly, aberrant SKP1 and SCF complex expression and function is expected to disrupt these essential pathways, which may have pathological implications in diseases like cancer. In this review, we summarize the central role SKP1 plays in regulating essential cellular processes; we describe functional models in which SKP1 expression is altered and the corresponding impacts on genome stability; and we discuss the prevalence of SKP1 somatic copy number alterations, mutations, and altered protein expression across different cancer types, to identify a potential link between SKP1 and SCF complex dysfunction to chromosome/genome instability and cancer pathogenesis. Ultimately, understanding the role of SKP1 in driving chromosome instability will expand upon our rudimentary understanding of the key events required for genome/chromosome stability that may aid in our understanding of cancer pathogenesis, which will be critical for future studies to establish whether SKP1 may be useful as prognostic indicator or as a therapeutic target.

DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

“…Through this mechanism, FBXO32 negatively regulates SKP1 activity, which may influence cell cycle progression and other cellular processes relevant to glioma development. Although the roles of SKP1 in chromosome instability have been largely revealed, 21,22 interestingly, the previous study has demonstrated that SKP1 acts as a tumor promoter via enhancing colorectal cancer stemness, 23 this is consistent with our results showing its promoting effects in glioma progression as tumor stemness has been elucidated as one of the root of tumor progression. 24 The identification of the FBXO32-SKP1 axis provides new insights into the regulation of glioma cell behaviors and offers a potential avenue for therapeutic intervention.…”

Identification of mitophagy-related hub genes during the progression of spinal cord injury by integrated multinomial bioinformatics analysis

“…The signature genes SKP1 and BAP1were identified and validated in this study. SKP1, a part of the E3 ubiquitin ligase complex that leads to protein degradation, plays an important role in maintaining genome and chromosome stability [ 44 , 45 ]. It is downregulated in the brains of patients with sporadic Parkinson’s disease (PD) and plays a neuroprotective role in the adult brain [ 46 ].…”

Dynamic changes in the transcriptome of oocytes during adolescent-onset PCOS in mice

“…The markedly down-regulated genes in the DHEA group mainly focused on cell cycle. S-phase Kinase-Associated Protein1 (SKP1) is a core component of the Skp, Cullin, F-box containing complex, an E3 ubiquitin ligase that participates in a variety of cellular processes (THOMPSON et al 2022). It was reported that reduced SKP1 expression induced chromosomal instability in both benign and malignant tumors (LEPAGE et al 2021).…”