BTG3, a candidate tumor suppressor, promotes methylation of checkpoint kinase CHK1

Abstract

B-cell translocation gene 3 (BTG3), recognized as a member of an antiproliferative B-cell translocation gene/Transducer of ErbB2 (BTG/Tob) gene family, is a downstream target of p53 and is induced upon genotoxic stress in a p53 and Checkpoint kinase 1 (CHK1), a vital checkpoint kinase which contributes significantly in cell survival and cell cycle checkpoints, dependent manner. Post-translational modifications of CHK1 (phosphorylation and ubiquitination) facilitated by interaction with BTG3 have been observed suggesting their possible role in tumorigenesis, although the underlying mechanisms are unclear. Methylation, as one of the types of post-translational modifications, is a critical event during cell cycle checkpoint controls and DNA damage repair. Here, for the first time, it is reported that overexpression of BTG3 vividly enhances the methylation of CHK1. Expression of CHK1 was detected in a cancer cell line in this study. This work also reveals the significant role of the kinase domain of CHK1 for BTG3 facilitated methylation as BTG3 overexpression only promoted the methylation of wild type CHK1 but failed to promote the methylation of CHK1 mutants which were impaired for their kinase domain. This novel finding would therefore greatly enhance our understanding of the mechanisms underlying interactions between important cancer biomarkers.