Ubiquitin Ligase Complexes in Cancer Biology

Ubiquitin ligase complexes, particularly those centred on Cullin-RING E3 ligases, orchestrate the selective degradation of regulatory proteins that govern cell cycle progression, DNA repair, signal transduction and transcriptional programmes. In cancer, dysregulation of these complexes—through overexpression, mutation or altered adaptor specificity—can subvert proteostasis to favour proliferation, survival and invasion. The Cullin4 family (CUL4A and CUL4B), in concert with the adaptor protein DDB1 and a spectrum of substrate receptors (DCAFs), executes monoubiquitination of histones or polyubiquitination of cyclins, checkpoint proteins and transcription factors, thereby influencing epigenetic landscapes and checkpoint integrity. Aberrant activation of these ligases has been linked to attenuation of DNA damage responses, epigenetic silencing of tumour suppressor miRNAs and promotion of epithelial–mesenchymal transition. Emerging evidence highlights the therapeutic potential of targeting neddylation pathways, modulating substrate recognition modules or inhibiting specific ligase–substrate interactions to restore cell-cycle checkpoints and impede metastatic dissemination.

Research from Nature Portfolio

Recent studies have illuminated a context-dependent role of CUL4B in modulating the response of normal tissues to genotoxic stress. In models of ionizing radiation injury to the intestinal epithelium, CUL4B was shown to dissociate from its cytoplasmic partner and relocalise to sites of DNA damage. Prior to irradiation, CUL4B suppressed ubiquitination of a proteasome activator, limiting p53-mediated apoptosis. Following DNA damage, phosphorylated CUL4B impeded homologous recombination by interfering with BRCA1 and RAD51 activation, thereby amplifying p53-dependent cell death. These findings reveal that dynamic control of CUL4B activity influences tissue resilience after radiotherapy and suggest strategies to protect normal epithelium during cancer treatment.

Ubiquitin Ligase Complexes in Cancer Biology publication trend

The graph below shows the total number of articles in ubiquitin ligase complexes in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Cullin-RING E3 ubiquitin ligase (CRL): A multiprotein complex that catalyses transfer of ubiquitin from E2 enzymes to target proteins, marking them for degradation.

Neddylation: The covalent attachment of the ubiquitin-like modifier NEDD8 to cullin scaffolds, activating the ligase complex.

DDB1-CUL4 associated factor (DCAF): A substrate‐recruiting adaptor within CRL4 complexes that determines specificity for target proteins.

Monoubiquitination: Conjugation of a single ubiquitin to a histone or non-histone substrate, often regulating transcription or chromatin state rather than degradation.

Epigenetic repression: Modulation of gene expression by post-translational histone modifications that influence chromatin accessibility without altering DNA sequence.

References

1. Dynamic role of CUL4B in radiation-induced intestinal injury-regeneration. Scientific Reports (2024).
2. Dysregulation of the miR‐194–CUL4B negative feedback loop drives tumorigenesis in non‐small‐cell lung carcinoma. Molecular Oncology (2017).
3. CUL4B contributes to cancer stemness by repressing tumor suppressor miR34a in colorectal cancer. Oncogenesis (2020).
4. Cul4B promotes the progression of ovarian cancer by upregulating the expression of CDK2 and CyclinD1. Journal of Ovarian Research (2020).
5. Pathogenic Role of the CRL4 Ubiquitin Ligase in Human Disease. Frontiers in Oncology (2012).