UBR5 (Ubiquitin-Protein Ligase E3 Component N-Recognin 5), also known as E3 ubiquitin-protein ligase UBR5 or EDD1, is a HECT-type E3 ubiquitin ligase located on chromosome 8q22.3. It is a member of the N-recognin family of E3 ligases, which recognize substrates bearing N-terminal (N-end rule) degradation signals["@ubr"]. UBR5 plays critical roles in protein quality control, cell cycle regulation, DNA damage response, and has been implicated in neurodegenerative diseases.
Function
UBR5 is a HECT-domain E3 ubiquitin ligase with multiple cellular functions:
N-End Rule Pathway
The N-end rule pathway recognizes proteins based on their N-terminal amino acid residues. UBR5:
Binds to destabilizing N-terminal residues
Polyubiquitinates target proteins for proteasomal degradation
Regulates short-lived regulatory proteins
Protein Quality Control
UBR5 is essential for clearing misfolded and damaged proteins:
Targets aberrant proteins for degradation
Prevents accumulation of toxic protein aggregates
Maintains proteostasis
DNA Damage Response
UBR5 plays important roles in DNA repair:
Regulates checkpoint kinases
Controls DNA repair protein levels
Maintains genome stability
Cell Cycle Regulation
UBR5 controls cell cycle progression:
Degrades cell cycle inhibitors
Regulates cyclins and CDKs
Ensures proper cell division
Disease Associations
Amyotrophic Lateral Sclerosis (ALS)
UBR5 has been implicated in ALS pathogenesis[@ubra]:
Dysregulated protein clearance — UBR5 dysfunction may impair [ubiquitin-proteasome system](/cell-types/ubiquitin-proteasome-system)
DNA damage accumulation — UBR5 deficiency may lead to increased DNA damage in motor [neurons](/entities/neurons)
Interaction with ALS genes — potential overlap with [TDP-43](/mechanisms/tdp-43-proteinopathy) and FUS pathways
Aggregation susceptibility — impaired degradation of aggregation-prone proteins
Cancer
UBR5 is frequently amplified or overexpressed in cancers:
Breast cancer
Ovarian cancer
Prostate cancer
Glioblastoma
It functions as an oncogene, promoting:
Cell proliferation
Metastasis
Therapy resistance
Neurodevelopmental Disorders
UBR5 variants have been associated with:
Intellectual disability
Developmental delay
Autism spectrum disorders
Expression Pattern
UBR5 is ubiquitously expressed with highest levels in: