| Title | HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence |
| Authors | Pan, Kewu Chen, Yifan Roth, Mendel Wang, Weibin Wang, Shuya Yee, Amy S. Zhang, Xiaowei |
| Affiliation | Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China. Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. |
| Keywords | INDUCED PREMATURE SENESCENCE TUMOR-SUPPRESSOR FACTOR HBP1 RETINOBLASTOMA PROTEIN CYCLE REGULATION REPRESSOR HBP1 DNMT1 PROTEIN BREAST-CANCER LIFE-SPAN METHYLATION |
| Issue Date | 2013 |
| Publisher | molecular and cellular biology |
| Citation | MOLECULAR AND CELLULAR BIOLOGY.2013,33,(5),887-903. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/343063 |
| ISSN | 0270-7306 |
| DOI | 10.1128/MCB.00637-12 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 医学部待认领 |
