Coiled-coil domain-containing protein 6 (CCDC6)

Coiled-coil domain-containing protein 6 (CCDC6) is a ubiquitously expressed, 475-amino acid phosphoprotein encoded by the CCDC6 gene on chromosome 10q21. It forms characteristic coiled-coil structural motifs enabling protein oligomerization and dimerization, with additional domains supporting protein-protein interaction, including an SH3-binding region. CCDC6 plays a critical role in DNA damage-induced apoptosis, cell cycle checkpoint regulation, and negative regulation of transcription via CREB1 repression. It acts as a tumor suppressor by maintaining proper DNA repair response, especially through homologous recombination; its loss leads to dysfunctional checkpoint control, error-prone DNA repair, and enhanced cellular survival following genotoxic stress. Pathologically, CCDC6 is most notable for forming gene fusions with RET kinase (CCDC6-RET) in papillary thyroid carcinoma (PTC) and lung adenocarcinomas, resulting in constitutive activation of the Ras/MAPK signaling pathway and oncogenic transformation. In these contexts, the fusion protein's unique ability to undergo phase separation facilitates assembly of membraneless signaling complexes, amplifying oncogenic signaling. CCDC6 itself is not currently considered a direct therapeutic target, but detecting CCDC6-RET gene rearrangements serves as a clinically actionable biomarker, identifying patients eligible for therapy with RET inhibitors.

Other names

D10S170TST1PTCTPCH4PTC1papillary thyroid carcinoma-encoded proteinProtein H4transforming sequence thyroid-1thyroid papillary carcinoma genecoiled-coil domain containing 6

RET inhibitors block kinase activity of RET–CCDC6 fusion proteins, thereby inhibiting constitutive downstream MAPK pathway signaling