- UBE2B (Ubiquitin-conjugating enzyme E2 B), also known as Rad6B, is a highly conserved member of the E2 ubiquitin-conjugating enzyme family with critical roles in DNA repair, cell cycle regulation, spermatogenesis, and protein quality control.
- Together with its close homolog UBE2A (Rad6A), UBE2B is considered one of the most ancient E2 enzymes, preserved from yeast to humans. Its primary function is to conjugate ubiquitin to specific substrates in cooperation with various E3 ligases, thereby modifying protein stability, localization, or activity.
- One of the most well-established functions of UBE2B is in the DNA damage tolerance pathway. It works with the E3 ligase RAD18 to monoubiquitinate proliferating cell nuclear antigen (PCNA), a key sliding clamp involved in DNA replication. This ubiquitination event allows the recruitment of translesion DNA synthesis (TLS) polymerases, which can bypass DNA lesions during replication. By enabling DNA synthesis across damaged templates, UBE2B ensures continued replication under stress and helps maintain genome stability. Additionally, UBE2B participates in post-replication repair and other DNA repair mechanisms, positioning it as a central guardian of genomic integrity.
- Beyond DNA repair, UBE2B is important in cell cycle progression and spermatogenesis. In germ cells, UBE2B expression is particularly high, and knockout studies in mice have demonstrated that loss of UBE2B leads to male infertility due to defective spermatogenesis. This essential role highlights its importance not only for genome maintenance but also for reproductive success. In somatic cells, UBE2B also contributes to histone ubiquitination, particularly of histone H2B, which impacts chromatin dynamics, transcriptional regulation, and epigenetic modifications.
- Clinically, aberrant regulation of UBE2B has been associated with cancer development, neurodegeneration, and infertility. Overexpression of UBE2B has been reported in several cancers, where it may contribute to genomic instability and tumor progression by altering DNA repair capacity and transcriptional control. On the other hand, deficiencies in UBE2B function can compromise DNA repair efficiency, making cells more vulnerable to genotoxic stress, which may contribute to neurodegenerative disorders. Because of its central role in DNA damage response, UBE2B is being investigated as a potential target for cancer therapy, particularly in tumors reliant on translesion synthesis and DNA repair plasticity.
- Structurally, UBE2B contains the conserved ubiquitin-conjugating (UBC) catalytic domain with its essential active-site cysteine, enabling thioester bond formation with ubiquitin. It lacks large N- or C-terminal extensions, making it structurally streamlined but highly versatile. Despite its structural simplicity, UBE2B achieves functional specificity through its interactions with particular E3 ligases such as RAD18, BRE1 (for histone H2B ubiquitination), and others. These partnerships allow UBE2B to function across multiple cellular pathways, from DNA repair to transcriptional regulation.
- In summary, UBE2B (Rad6B) is a multifunctional E2 enzyme with critical roles in DNA repair, chromatin regulation, cell cycle progression, and spermatogenesis. Its cooperation with specific E3 ligases enables processes such as PCNA ubiquitination during DNA damage tolerance and histone ubiquitination during transcriptional control. Dysregulation of UBE2B has broad implications, contributing to cancer progression, neurodegeneration, and infertility. Given its central role in genome maintenance and reproduction, UBE2B represents both a fundamental regulator of cellular stability and a potential therapeutic target in oncology and beyond.
Reliability Index *****
Note: If you notice any errors or inconsistencies, we welcome your feedback. Please share your observations in the comment box below — your input helps us improve.
Highest reliability: *****
Lowest reliability: *****
