- UBE2T (Ubiquitin-conjugating enzyme E2 T) is a specialized member of the E2 ubiquitin-conjugating enzyme family, best known for its critical role in the Fanconi anemia (FA) DNA repair pathway.
- Like other E2 enzymes, UBE2T functions by receiving activated ubiquitin from an E1 ubiquitin-activating enzyme and then working with an E3 ubiquitin ligase to transfer ubiquitin to specific protein substrates. What makes UBE2T unique is its strict involvement in repairing DNA interstrand crosslinks (ICLs), one of the most dangerous types of DNA damage that can block replication and transcription.
- In the FA pathway, UBE2T partners with the FA core complex E3 ligase, which includes the FANCL subunit. Together, UBE2T and FANCL catalyze the monoubiquitination of FANCD2 and FANCI, two key proteins that form the FANCI–FANCD2 (ID) complex. This modification activates the complex and allows it to recruit downstream repair proteins to the site of DNA damage. Without UBE2T-mediated ubiquitination, the FA pathway fails to function properly, leaving cells unable to resolve interstrand crosslinks. This results in genomic instability, hypersensitivity to DNA-damaging agents, and an increased risk of bone marrow failure and cancer.
- Genetically, mutations in UBE2T cause Fanconi anemia subtype D1 (FA-D1), a rare autosomal recessive disorder. Individuals with FA-D1 typically present with bone marrow failure, congenital anomalies (such as skeletal malformations, microcephaly, or kidney defects), growth retardation, and increased predisposition to acute myeloid leukemia and other cancers. Cellular studies of FA-D1 patients show defective FANCD2 monoubiquitination, confirming the essential role of UBE2T in this process. Because FA-D1 is extremely rare, only a small number of patients have been described worldwide, but the phenotype aligns closely with that of other FA subtypes.
- Beyond its canonical role in the FA pathway, UBE2T has also been implicated in cancer biology. Elevated UBE2T expression has been observed in several cancers, including breast, prostate, gastric, and lung cancers. In these contexts, UBE2T may promote tumor growth by enhancing DNA repair capacity in cancer cells, supporting uncontrolled proliferation, or by ubiquitinating proteins outside of the FA pathway that influence oncogenic signaling. As such, UBE2T is under investigation as a potential biomarker and therapeutic target in oncology.
- Structurally, UBE2T contains the conserved ubiquitin-conjugating (UBC) catalytic domain, including an active-site cysteine that forms a thioester intermediate with ubiquitin. Unlike many generalist E2 enzymes that can work with multiple E3 ligases, UBE2T shows strong substrate and partner specificity, primarily acting with FANCL to target FANCD2 and FANCI. This specialization reflects its evolutionary refinement for DNA repair fidelity.
- In summary, UBE2T is a highly specialized E2 ubiquitin-conjugating enzyme that ensures proper DNA interstrand crosslink repair through the Fanconi anemia pathway. Loss-of-function mutations in UBE2T cause Fanconi anemia subtype D1, while overexpression has been linked to tumorigenesis. Its dual importance in both rare genetic disease and common cancers highlights UBE2T as a key player in genome stability and a promising target for therapeutic research.
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