Ubiquitin Ligase Mediated DNA Repair Mechanisms

Ubiquitin ligases are pivotal in safeguarding genome integrity by covalently attaching ubiquitin to proteins involved in the detection, signalling and resolution of DNA lesions. Among these, cullin–RING ligases (CRLs) constitute the largest E3 family, using a cullin scaffold and a repertoire of substrate receptors to direct ubiquitination. In the context of DNA repair, CRLs regulate the turnover and chromatin recruitment of key factors across multiple pathways: non-homologous end joining (NHEJ) and homologous recombination (HR) for double-strand breaks, mismatch repair (MMR) for replication errors, and nucleotide excision repair (NER) for helix-distorting lesions. Beyond proteasomal degradation, ubiquitin tags act as dynamic signals that modulate protein–protein interactions, influence repair complex assembly and coordinate the timely removal of obstacles to replication. Dysregulation of these ligases underlies genomic instability and contributes to oncogenesis, highlighting their importance as both fundamental regulators and therapeutic targets.

Research from Nature Portfolio

Recent studies have shown that in antiviral CD8⁺ T cells, the transcription factor c-Myc drives the expression of the E3 ligase Cullin 4B, which in turn limits replication stress by targeting cell-cycle regulators for ubiquitination. Loss of Cullin 4B in these lymphocytes results in accumulation of DNA damage markers, failure to clear infection and proliferative collapse, illustrating a direct link between immune activation and genome maintenance. A foundational investigation has further characterised a CRL4B–DDB1–DCAF11 complex that selectively ubiquitinates the cyclin-dependent kinase inhibitor p21 at multiple lysine residues, promoting its proteasomal degradation during S phase. This controlled removal of p21 is essential to prevent unscheduled cell-cycle arrest and ensures high-fidelity replication, underlining the role of ubiquitin ligases in coordinating DNA synthesis with repair.

Ubiquitin Ligase Mediated DNA Repair Mechanisms publication trend

The graph below shows the total number of articles in ubiquitin ligase mediated dna repair mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Ubiquitin ligase (E3): Enzyme that catalyses the transfer of ubiquitin onto specific protein substrates, marking them for degradation or altering their activity.

Cullin–RING ligase (CRL): Multiprotein E3 complex built on a cullin scaffold and RING domain, with interchangeable substrate receptors that determine target specificity.

DDB1–CUL4-associated factor (DCAF): WD40‐containing adaptor that binds to DDB1 within the CRL4 complex and recruits particular substrates for ubiquitination.

Proliferating cell nuclear antigen (PCNA): Ring‐shaped clamp that encircles DNA, coordinating replication and repair by serving as a platform for factor recruitment.

Non-homologous end joining (NHEJ): Double-strand break repair pathway that ligates DNA ends directly, functioning throughout the cell cycle but at the cost of potential sequence loss.

Homologous recombination (HR): High-fidelity repair mechanism that uses a sister chromatid as a template to accurately restore broken DNA.

Mismatch repair (MMR): Process that recognises and corrects base mismatches and small loops introduced during replication, preserving genomic fidelity.

References

1. c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity. Nature Communications (2023).
2. CRL4BDCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells. Scientific Reports (2017).
3. CDK-independent role of D-type cyclins in regulating DNA mismatch repair. Molecular Cell (2024).
4. RUVBL1 ubiquitination by DTL promotes RUVBL1/2-β-catenin-mediated transcriptional regulation of NHEJ pathway and enhances radiation resistance in breast cancer. Cell Death & Disease (2024).
5. Pulse-SILAC and Interactomics Reveal Distinct DDB1-CUL4–Associated Factors, Cellular Functions, and Protein Substrates. Molecular & Cellular Proteomics (2023).