HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence
HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence
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HBP1介导的DNA甲基转移酶1转录调控及其对细胞衰老的影响
DOI：
10.1128/mcb.00637-12
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发表时间：
2013-03-01
影响因子：
5.3
通讯作者：
Zhang, Xiaowei
中科院分区：
文献类型：
--
作者：
Pan, Kewu;Chen, Yifan;Zhang, Xiaowei
DNA 甲基转移酶 1 (DNMT1) 的活性与多种生物活性相关，包括细胞增殖、衰老和癌症发展。在这项研究中，我们证明了 HMG 盒蛋白 1 (HBP1) 转录因子是衰老过程中复杂机制中 DNMT1 的新抑制因子。 DNMT1 基因在转录起始位点的 -115 至 -134 bp 处包含 HBP1 结合位点。 HBP1 通过序列特异性结合抑制内源性 DNMT1 基因，导致基因特异性（例如 p16(INK4)）和整体 DNA 低甲基化变化。 DNMT1 介导的 HBP1 介导的抑制导致复制和过早衰老，后者可由 Ras 和 HBP1 本身诱导。一项详细的研究出乎意料地揭示了 HBP1 具有双重且复杂的转录功能，这两种功能都会导致过早衰老。在过早衰老过程中，HBP1 既抑制 DNMT1 基因，又激活 p16 基因。相反的转录功能通过不同的DNA序列和不同的蛋白质乙酰化进行。虽然 HBP1 和 DNMT1 之间的相互关系错综复杂，但它具有特殊的重要性，因为它的废除会损害衰老并促进肿瘤发生。总之，我们的结果表明，HBP1 转录因子在细胞衰老过程中对关键基因进行复杂的调控，对整体 DNA 甲基化状态产生影响。
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.