A novel interaction between MNT and CCDC6: structural insights and distinct roles in cell migration and the DNA damage response

MNT is a transcription factor of the MYC-MAX-MXD network whose biological functions remain incompletely understood. Here, we identify CCDC6, a tumor suppressor involved in the DNA damage response (DDR), as a novel MNT-interacting protein. Co-immunoprecipitation and interaction mapping analyses identified a part of the CCDC6 coiled-coil domain and the MNT bHLH-LZ region as major determinants of binding. Structural modelling further identified MNT residues predicted to mediate CCDC6 binding that are also critical for MNT-MAX dimerization. Transcriptomic analyses revealed substantial overlap between the gene expression programs regulated by MNT and CCDC6. Loss of either protein promoted cell migration, whereas MNT and CCDC6 cooperated in the regulation of {gamma}H2AX signalling, cisplatin responses and CCDC6 localization during the DDR. Together, our findings uncover a previously unrecognized connection between CCDC6 and the MYC-MAX-MXD network through its interaction with MNT, revealing an additional layer of regulation within this transcriptional network.