TIMELESS Circadian Regulator Gene
Essential component of the circadian clock and DNA damage response pathway
Gene Information Card
| Symbol | TIMELESS |
|---|---|
| Full Name | timeless circadian regulator |
| Gene Type | protein-coding |
| Chromosomal Location | 12q13.3 |
| NCBI Gene ID | 8914 ncbi.nlm.nih.gov/gene/8914 |
| Ensembl ID | ENSG00000111602 |
| UniProt ID | Q9UNS1 |
| OMIM ID | 603887 |
| HGNC ID | 11813 |
| Aliases | TIM, TIM1, hTIM, timeless homolog (Drosophila) |
Description
TIMELESS encodes a protein that is a core component of the circadian clock, regulating daily rhythms in behavior and physiology. It also plays a critical role in the DNA damage response, cell cycle checkpoint control, and chromatin remodeling. The protein interacts with PERIOD and CRYPTOCHROME to form a repressor complex that inhibits CLOCK-BMAL1-mediated transcription. Additionally, TIMELESS is involved in replication fork stability and the intra-S phase checkpoint.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast Cancer | Overexpression of TIMELESS disrupts circadian rhythm and promotes cell proliferation; associated with poor prognosis. | PMID: 23431173; COSMIC |
| Colorectal Cancer | TIMELESS upregulation correlates with tumor progression and chemoresistance via DNA damage repair enhancement. | PMID: 25652252; COSMIC |
| Lung Cancer | Elevated TIMELESS expression linked to increased genomic instability and resistance to platinum-based therapy. | PMID: 27270425; COSMIC |
| Sleep Disorders | Variants in TIMELESS may contribute to circadian rhythm sleep disorders, including advanced sleep phase syndrome. | OMIM: 603887; ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | High |
| Bone Marrow | 12.8 | High |
| Lymph Node | 11.5 | High |
| Brain (Cerebellum) | 9.1 | Medium |
| Heart | 7.3 | Medium |
| Liver | 5.6 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 14.1 | Cervical cancer cell line; high expression |
| A549 | 12.3 | Lung adenocarcinoma; moderate-high |
| MCF7 | 11.8 | Breast cancer; elevated |
| HEK293 | 9.5 | Embryonic kidney; moderate |
| K562 | 13.0 | Leukemia; high |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1072C>T (p.Arg358Trp) | Missense | 0.01% (gnomAD) | Alters protein stability; potential loss of circadian function |
| c.1543G>A (p.Gly515Arg) | Missense | 0.005% (gnomAD) | May affect DNA damage response interaction |
| c.1966_1967insA (p.Thr656Asnfs*2) | Frameshift | <0.001% | Loss-of-function; truncation of C-terminal domain |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the protein, impairing circadian repressor activity and DNA damage checkpoint function.
Gain of Function (GOF)
Not well characterized; overexpression in cancers suggests potential oncogenic gain-of-function via enhanced cell cycle progression.
Dominant Negative (DN)
Missense variants in the protein interaction domains may disrupt complex formation with PERIOD or TIMELESS-interacting protein (TIPIN), leading to dominant-negative effects on circadian rhythm.
View complete mutation data：
Gene Ontology (GO)
| • circadian rhythm | • DNA damage response |
| • signal transduction by p53 class mediator | • chromatin remodeling |
| • cell cycle checkpoint | • protein binding |
| • transcription repressor complex |
Pathways
• Circadian Clock (KEGG: hsa04710)
• Cell Cycle Checkpoints (Reactome: R-HSA-69620)
• DNA Damage Bypass (Reactome: R-HSA-73893)
Protein Summary
The TIMELESS protein (UniProt Q9UNS1) is 1,208 amino acids long and contains a conserved TIMELESS domain. It forms a heterodimer with TIPIN to stabilize replication forks and interacts with PER, CRY, and CLOCK-BMAL1 to regulate circadian transcription. The protein shuttles between nucleus and cytoplasm and is phosphorylated in a cell cycle-dependent manner.
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