TIMELESS-interacting protein (TIPIN) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''TIPIN'' gene.

Structure

TIPIN is a relatively small protein that lacks known enzymatic activity and functions primarily through protein-protein interactions. It forms a stable complex with TIMELESS, a binding interaction that is essential for its role in the replication stress response. Crystallographic and structural studies have confirmed direct interactions between TIPIN, TIMELESS, and other components of the replication machinery. TIPIN contains a central core region, predominantly

alpha-helical An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

and spanning amino acids 57–160, which is both necessary and sufficient for stable binding to TIMELESS. Structural analyses, including studies of the yeast orthologue Csm3, show that this region adopts a five-helix bundle that interfaces with the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

region of TIMELESS (Tof1 in yeast). This interaction is mediated through a

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

surface stabilized by

salt bridge In electrochemistry, a salt bridge or ion bridge is an essential laboratory device discovered over 100 years ago. It contains an electrolyte solution, typically an inert solution, used to connect the Redox, oxidation and reduction Half cell, ...

s. The N- and C-terminal tails of TIPIN are not required for complex formation, highlighting the central helical core as the primary structured domain involved. This structural configuration supports a scaffolding or mechanical role for TIPIN in replication fork stability and checkpoint activation. No additional structured domains have been identified beyond the central core, which is sufficient for its function within the replication fork protection complex.

Function

TIPIN forms a heterodimeric complex with the TIMELESS (TIM) protein and plays a central role in

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...

and the stabilization of replication forks under normal and stress conditions. This complex helps regulate the pace of replication fork movement and participates in the activation of the Intra-S-phase checkpoint in response to DNA damage. The TIPIN-TIM complex is essential for proper replication fork protection and coordination of DNA damage responses. TIPIN deficiency leads to stalled replication forks and increased chromosomal instability, highlighting its role in preserving genome integrity. Additionally, TIPIN helps mediate the ATR-CHK1 checkpoint pathway, which delays cell cycle progression in response to replication stress.

Interactions

TIPIN has been shown to interact with: * TIMELESS protein – forming a complex that is essential for DNA replication and checkpoint function. *

Replication protein A1 Replication protein A 70 kDa DNA-binding subunit is a protein that in humans is encoded by the ''RPA1'' gene. Interactions Replication protein A1 has been shown to interact with: * BRCA2, * BLM, * MCM2, * MCM4, * MCM6, * MCM7, * MU ...

(RPA1) – facilitating recruitment to stalled forks and checkpoint activation. * Claspin – involved in replication checkpoint signaling.

Clinical significance

Although no specific mutations in the ''TIPIN'' gene have been directly associated with human diseases, dysfunction of the TIPIN-TIM complex can compromise genome stability and is thus relevant in the context of cancer biology. TIPIN expression may also be altered in tumors with replication stress or deficient checkpoint control.

Structure

Function

Interactions

Clinical significance

References

Further reading