TIPIN

TIMELESS-interacting protein (TIPIN) is a protein that in humans is encoded by the TIPIN gene.^[5][6][7]

TIPIN
Identifiers
Aliases	TIPIN, TIMELESS interacting protein
External IDs	OMIM: 610716; MGI: 1921571; HomoloGene: 32373; GeneCards: TIPIN; OMA:TIPIN - orthologs
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q22.31 Start 66,336,191 bp[1] End 66,386,746 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 C|9 34.6 cM Start 64,188,863 bp[2] End 64,212,706 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gonad testicle Achilles tendon secondary oocyte right testis left testis ganglionic eminence ventricular zone islet of Langerhans sperm Top expressed in fetal liver hematopoietic progenitor cell medial ganglionic eminence mandibular prominence otic placode abdominal wall embryo maxillary prominence somite primitive streak ventricular zone More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding DNA binding Cellular component intracellular membrane-bounded organelle nucleus nucleoplasm cytoplasm replication fork protection complex Biological process cell cycle phase transition mitotic intra-S DNA damage checkpoint signaling cellular response to DNA damage stimulus cell division DNA replication checkpoint signaling regulation of nuclear cell cycle DNA replication positive regulation of cell population proliferation cell cycle replication fork arrest replication fork protection DNA damage checkpoint signaling response to UV DNA replication Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 54962 66131 Ensembl ENSG00000075131 ENSMUSG00000032397 UniProt Q9BVW5 Q91WA1 RefSeq (mRNA) NM_001289986 NM_017858 NM_001398281 NM_001398282 NM_001398283 NM_001398284 NM_001398285 NM_001398286 NM_001398287 NM_025372 NM_001324556 NM_001324557 NM_001324558 RefSeq (protein) NP_001276915 NP_060328 NP_001311485 NP_001311486 NP_001311487 NP_079648 Location (UCSC) Chr 15: 66.34 – 66.39 Mb Chr 9: 64.19 – 64.21 Mb PubMed search [3] [4]
Wikidata
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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.^[5][8]

TIPIN contains a central core region, predominantly alpha-helical and spanning amino acids 57–160, which is both necessary and sufficient for stable binding to TIMELESS.^[9] Structural analyses, including studies of the yeast orthologue Csm3, show that this region adopts a five-helix bundle that interfaces with the C-terminal region of TIMELESS (Tof1 in yeast). This interaction is mediated through a hydrophobic surface stabilized by salt bridges.^[9] 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.^[9] 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.^[9][10]

Function

TIPIN forms a heterodimeric complex with the TIMELESS (TIM) protein and plays a central role in DNA replication 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.^[6][11]

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.^[6][12]

Interactions

TIPIN has been shown to interact with:

• TIMELESS protein – forming a complex that is essential for DNA replication and checkpoint function.^[5]
• Replication protein A1 (RPA1) – facilitating recruitment to stalled forks and checkpoint activation.^[11]
• Claspin – involved in replication checkpoint signaling.^[13]

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.^[14][15]