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

Abstract

Mutations in the highly similar genes B-cell translocation gene 1 (BTG1) and BTG2 are identified in approximately 10–15% of non-Hodgkin lymphoma cases, which may suggest a direct involvement of BTG1 and BTG2 in 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 on in silico analysis. 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 in BTG1 may contribute to malignant transformation and tumor cell proliferation by interfering with its anti-proliferative activity and ability to interact with CNOT7 and CNOT8.