RIF1 Gene: Structure, Function, and Clinical Significance
A comprehensive guide to the RIF1 gene, its role in DNA repair, replication timing, and disease associations.
Gene Information Card
| Symbol | RIF1 |
|---|---|
| Full Name | Replication Timing Regulatory Factor 1 |
| Gene Type | Protein-coding |
| Chromosomal Location | 2q23.3 |
| NCBI Gene ID | 55183 ncbi.nlm.nih.gov/gene/55183 |
| Ensembl ID | ENSG00000180901 |
| UniProt ID | Q5T1R4 |
| OMIM ID | 617535 |
| HGNC ID | 26023 |
| Aliases | RIF1, Rap1 interacting factor 1 homolog, FLJ20174 |
Description
The RIF1 gene encodes a large, multi-domain protein that plays a critical role in DNA double-strand break (DSB) repair pathway choice, specifically promoting non-homologous end joining (NHEJ) by inhibiting homologous recombination (HR) in G1 phase. It also regulates DNA replication timing by organizing the genome into replication domains and is involved in telomere length regulation. RIF1 is essential for normal development and its dysregulation is linked to various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various types) | RIF1 mutations or altered expression can disrupt DNA repair, leading to genomic instability and tumorigenesis. Loss of RIF1 may impair NHEJ, increasing reliance on error-prone repair pathways. | COSMIC database lists somatic mutations in RIF1 across multiple cancer types; ClinVar reports pathogenic variants associated with cancer predisposition. |
| RIF1-related disorder (autosomal recessive) | Biallelic loss-of-function mutations in RIF1 cause a syndrome characterized by growth retardation, microcephaly, and intellectual disability, due to defective DNA repair and replication. | OMIM entry 617535; ClinVar lists pathogenic variants. |
| Immunodeficiency | RIF1 deficiency impairs V(D)J recombination, a process requiring NHEJ, leading to combined immunodeficiency. | Case reports and functional studies; OMIM. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 25.3 | High |
| Bone Marrow | 12.1 | Medium |
| Lymph Node | 10.5 | Medium |
| Brain | 8.2 | Medium |
| Liver | 5.4 | Low |
| Heart | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 15.0 | Moderate expression |
| K562 (leukemia) | 18.2 | High expression |
| MCF7 (breast cancer) | 9.8 | Moderate expression |
| HepG2 (liver cancer) | 6.3 | Low expression |
| A549 (lung cancer) | 11.4 | Moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412Ter) | Nonsense | Rare (0.01% in gnomAD) | Loss of function, leading to truncated protein and RIF1 deficiency |
| c.2345_2349del (p.Glu782fs) | Frameshift | Rare | Loss of function, associated with RIF1-related disorder |
| c.3456A>G (p.Ile1152Val) | Missense | Somatic in cancer (COSMIC) | Unknown functional impact; may affect protein stability |
| c.4567G>A (p.Asp1523Asn) | Missense | Somatic in cancer (COSMIC) | Potential gain-of-function or dominant-negative effect, not fully characterized |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (nonsense, frameshift, splice-site) lead to reduced or absent RIF1 protein, impairing NHEJ and replication timing, causing genomic instability and developmental defects.
Gain of Function (GOF)
No clear gain-of-function mutations have been reported; some missense variants may alter protein interactions but are not classified as gain-of-function.
Dominant Negative (DN)
Certain missense mutations in the HEAT repeat domains may exert dominant-negative effects by interfering with wild-type RIF1 function, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • DNA double-strand break repair | • Non-homologous end joining |
| • DNA replication timing | • Telomere maintenance |
| • Chromatin organization | • Protein binding |
| • Nucleus |
Pathways
• Non-homologous end joining (NHEJ) pathway
• Homologous recombination (HR) regulation
• DNA replication timing regulation
• Telomere length regulation
Protein Summary
The RIF1 protein is a large (approximately 250 kDa) nuclear protein containing HEAT repeat domains and a C-terminal domain that interacts with protein phosphatase 1 (PP1). It is recruited to DNA double-strand breaks by 53BP1 and counteracts BRCA1-mediated end resection, thereby promoting NHEJ. RIF1 also binds to chromatin and regulates replication timing by organizing replication domains. It is essential for normal development and immune system function.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| RIF1 Knockout HEK293 Cell Line | EDJ-KQ15072 | Human | 55183 | Details Get a Quote |
| RIF1 Knockout A-549 Cell Line | EDJ-KQ45632 | Human | 55183 | Details Get a Quote |
| RIF1 Knockout HCT 116 Cell Line | EDJ-KQ45633 | Human | 55183 | Details Get a Quote |
| RIF1 Knockout HeLa Cell Line | EDJ-KQ45634 | Human | 55183 | Details Get a Quote |
