Frequent loss of BTG1 activity and impaired interactions with the Caf1 subunit of the Ccr4-Not deadenylase in non-Hodgkin lymphoma

Mutations in the highly similar genes B-cell translocation gene 1 (BTG1) andBTG2are identified in approximately 10-15% of non-Hodgkin lymphoma cases, which may suggest a direct involvement ofBTG1andBTG2in malignant transformation. However, it is unclear whether or how disease-associated mutations impair the function of these genes. Therefore, we selected 16 BTG1 variants based onin silicoanalysis. We then evaluated (i) the ability of these variants to interact with the known protein-binding partners CNOT7 and CNOT8, which encode the Caf1 catalytic subunit of the Ccr4-Not deadenylase complex; (ii) the activity of the variant proteins in cell cycle progression; (iii) translational repression; and (iv) mRNA degradation. Based on these analyses, we conclude that mutations inBTG1may contribute to malignant transformation and tumor cell proliferation by interfering with its anti-proliferative activity and ability to interact with CNOT7 and CNOT8.