RNF168: E3 Ubiquitin-Protein Ligase in DNA Damage Response
Key regulator of histone ubiquitination and double-strand break repair
Gene Information Card
| Symbol | RNF168 |
|---|---|
| Full Name | Ring Finger Protein 168 |
| Gene Type | Protein coding |
| Chromosomal Location | 3q29 |
| NCBI Gene ID | 165918 ncbi.nlm.nih.gov/gene/165918 |
| Ensembl ID | ENSG00000163961 |
| UniProt ID | Q8IYW5 |
| OMIM ID | 612688 |
| HGNC ID | 26685 |
| Aliases | RNF168, hRNF168, FLJ20184, MGC33887 |
Description
RNF168 encodes an E3 ubiquitin-protein ligase that plays a central role in the DNA damage response (DDR). It is recruited to sites of double-strand breaks (DSBs) where it ubiquitinates histones H2A and H2AX, promoting the accumulation of repair factors such as 53BP1 and BRCA1. RNF168 activity is essential for efficient homologous recombination and non-homologous end joining. Loss-of-function mutations cause RIDDLE syndrome, characterized by radiosensitivity, immunodeficiency, and genomic instability. RNF168 is also implicated in breast cancer susceptibility and other malignancies.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| RIDDLE syndrome | Loss-of-function mutations impair histone ubiquitination, disrupting DSB repair and checkpoint activation | OMIM #611943; ClinVar |
| Breast cancer | RNF168 deficiency leads to genomic instability and increased risk; rare variants associated with familial breast cancer | NCBI Gene; COSMIC |
| Immunodeficiency | Defective V(D)J recombination due to impaired DNA repair in lymphocytes | OMIM; ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 12.5 | Medium |
| Bone marrow | 8.3 | Medium |
| Lymph node | 7.1 | Medium |
| Brain | 4.2 | Low |
| Liver | 3.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 15.2 | High expression in embryonic kidney cells |
| HeLa | 10.6 | Cervical carcinoma line |
| MCF7 | 9.4 | Breast cancer line |
| K562 | 7.8 | Leukemia line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1196G>A (p.Trp399*) | Nonsense | Rare | Loss of function; truncation of RING domain |
| c.1552C>T (p.Arg518*) | Nonsense | Rare | Loss of function; associated with RIDDLE syndrome |
| c.1A>G (p.Met1?) | Missense | Rare | Loss of function; start codon loss |
| c.205C>T (p.Arg69Trp) | Missense | Rare | Likely loss of function; disrupts ubiquitin binding |
Mutation functional classification
Loss of Function (LOF)
Nonsense and frameshift mutations that truncate the protein or disrupt the RING finger domain abolish E3 ligase activity, leading to defective DNA repair and genomic instability.
Gain of Function (GOF)
No gain-of-function mutations have been reported for RNF168.
Dominant Negative (DN)
No dominant-negative mutations have been characterized; RNF168 acts in a recessive manner in RIDDLE syndrome.
View complete mutation data：
Gene Ontology (GO)
Pathways
• DNA double-strand break repair via homologous recombination (Reactome R-HSA-5693568)
• DNA double-strand break repair via non-homologous end joining (Reactome R-HSA-5693571)
• Ubiquitin-mediated proteolysis (KEGG hsa04120)
• p53 signaling pathway (KEGG hsa04115)
Protein Summary
RNF168 is a 571-amino acid E3 ubiquitin ligase containing a RING finger domain, two ubiquitin-binding domains (UBA and MIU), and a nuclear localization signal. It catalyzes the formation of K63-linked ubiquitin chains on histones H2A and H2AX at DNA damage sites, creating a platform for the recruitment of downstream repair factors. The protein is essential for the G2/M checkpoint and for maintaining genomic stability. Structural studies show that the RING domain coordinates zinc ions and mediates interaction with E2 ubiquitin-conjugating enzymes.
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