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 (<i>BTG1</i>) and <i>BTG2</i> are identified in approximately 10-15% of non-Hodgkin lymphoma cases, which may suggest a direct involvement of <i>BTG1</i> and <i>BTG2</i> 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 <i>in silico</i> 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 <i>BTG1</i> may contribute to malignant transformation and tumor cell proliferation by interfering with its anti-proliferative activity and ability to interact with CNOT7 and CNOT8.