title: Candidate tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked ubiquitination and activation of the checkpoint kinase CHK1.
abstract: B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG/ Transducer of ErbB2 gene family and is induced by genotoxic stress in a p53- and Checkpoint kinase 1 (CHK1)-dependent manner. Down-regulation of BTG3 has been observed in human cancers, suggesting that it plays an important role in tumor suppression, although the underlying mechanisms are unclear. Here, we report that BTG3 interacts with CHK1, a key effector kinase in the cell cycle checkpoint response, and regulates its phosphorylation and activation. Upon interaction, BTG3 mediates K63-linked ubiquitination of CHK1 at Lys132 through the cullin-RING ligase 4(Cdt2) E3 complex, thus facilitating CHK1 chromatin association. We show that BTG3-depleted cells phenocopy those CHK1-deficient cells, exhibiting increased cell death after replication block and impaired chromosome alignment and segregation. These defects could be corrected by wild-type BTG3 but not by a mutant impaired in CHK1 interaction. We propose that BTG3-dependent CHK1 ubiquitination contributes to its chromatin localization and activation and that a defect in this regulation may increase genome instability and promote tumorigenesis.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Yu-Che
authors.initials: YC
authors.lastname: Cheng
authors.forename: Tsong-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: Sheau-Yann
authors.initials: SY
authors.lastname: Shieh
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D015536:Down-Regulation; D005786:Gene Expression Regulation; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000235:genetics; D008938:Mitosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D008941:Spindle Apparatus; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D014466:Ultraviolet Rays
chemical_list: C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D011506:Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D046988:Proteasome Endopeptidase Complex; D008239:Lysine