title: HBP1-mediated transcriptional regulation of DNA methyltransferase 1 and its impact on cell senescence.
abstract: The activity of DNA methyltransferase 1 (DNMT1) is associated with diverse biological activities, including cell proliferation, senescence, and cancer development. In this study, we demonstrated that the HMG box-containing protein 1 (HBP1) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence. The DNMT1 gene contains an HBP1-binding site at bp -115 to -134 from the transcriptional start site. HBP1 repressed the endogenous DNMT1 gene through sequence-specific binding, resulting in both gene-specific (e.g., p16(INK4)) and global DNA hypomethylation changes. The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence, the latter of which could be induced by Ras and HBP1 itself. A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions, both of which contribute to premature senescence. HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence. The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation. While intricate, the reciprocal partnership between HBP1 and DNMT1 has exceptional importance, since its abrogation compromises senescence and promotes tumorigenesis. Together, our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence, with an impact on overall DNA methylation state.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Kewu
authors.initials: K
authors.lastname: Pan
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.forename: Mendel
authors.initials: M
authors.lastname: Roth
authors.forename: Weibin
authors.initials: W
authors.lastname: Wang
authors.forename: Shuya
authors.initials: S
authors.lastname: Wang
authors.forename: Amy S
authors.initials: AS
authors.lastname: Yee
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D002460:Cell Line; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D019942:Genes, p16; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human