TIMELESS
Domain
Residues 1182-1199 comprise a putative nuclear localization signal; nuclear localization is required for the regulation of period length of the circadian clock.
The DNA-binding domain (residues 816-954) binds to both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and has high affinity for DNA sequences rich in guanine that form G-quadruplex (G4) structures.
The C-terminal domain, comprising the DNA-binding domain and the PARP1-binding region, is required for the replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures.
Function
Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication, DNA repair and in the regulation of the circadian clock (PubMed:17141802, PubMed:17296725, PubMed:23359676, PubMed:23418588, PubMed:26344098, PubMed:31138685, PubMed:32705708, PubMed:35585232, PubMed:9856465). Required to stabilize replication forks during DNA replication by forming a complex with TIPIN: this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress (PubMed:17141802, PubMed:17296725, PubMed:23359676, PubMed:35585232). During DNA replication, inhibits the CMG complex ATPase activity and activates DNA polymerases catalytic activities, coupling DNA unwinding and DNA synthesis (PubMed:23359676). TIMELESS promotes TIPIN nuclear localization (PubMed:17141802, PubMed:17296725). Plays a role in maintaining processive DNA replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures, possibly together with DDX1 (PubMed:32705708). Involved in cell survival after DNA damage or replication stress by promoting DNA repair (PubMed:17141802, PubMed:17296725, PubMed:26344098, PubMed:30356214). In response to double-strand breaks (DSBs), accumulates at DNA damage sites and promotes homologous recombination repair via its interaction with PARP1 (PubMed:26344098, PubMed:30356214, PubMed:31138685). May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light (PubMed:15798197). Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock (PubMed:23418588, PubMed:31138685). Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus (PubMed:31138685, PubMed:9856465). May play a role as destabilizer of the PER2-CRY2 complex (PubMed:31138685). May also play an important role in epithelial cell morphogenesis and formation of branching tubules (By similarity).
Involvement in disease
Advanced sleep phase syndrome, familial, 4
FASPS4
An autosomal dominant disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms.
None
The disease is caused by variants affecting the gene represented in this entry.
Sequence Similarities
Belongs to the timeless family.
Tissue Specificity
Expressed in all tissues examined including brain, heart, lung, liver, skeletal muscle, kidney, placenta, pancreas, spleen, thymus and testis. Highest levels of expression in placenta, pancreas, thymus and testis.
Cellular localization
- Nucleus
- Chromosome
- In response to double-strand breaks (DSBs), accumulates at DNA damage sites via its interaction with PARP1.
Alternative names
TIM, TIM1, TIMELESS1, TIMELESS, Protein timeless homolog, hTIM