HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

Abstract

bThe 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 sequencespecific binding, resulting in both gene-specific (e.g., p16INK4 ) 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. Epigenetic alterations have essential roles in determining gene expression patterns and in setting the environment for activators or repressors to function appropriately. DNA methylation has been associated with cancer and senescence (1-4). Cellular senescence is characterized by a permanent cell cycle arrest and the acquisition of distinct morphological, physiological, and epigenetic changes in response to events such as telomere attrition, aberrant oncogene activation, or abrogation of tumor suppressor gene functions. Senescence is a tumor-suppressive process the abrogation of which enables the path to tumorigenesis (5-8). Although seemingly two distinct phenomena, cellular senescence and cancer share similarly altered global epigenetic profiles comprising complex changes in DNA methylation, involving both hypomethylation and hypermethylation of certain genes and sequences. The establishment of DNA methylation during DNA replication and DNA repair is catalyzed by a family of DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B). In particular, DNMT1 mRNA expression is significantly elevated in different cancers and is regarded as a maintenance methylase (9-11). In senescence, the levels of DNA methylation and DNMT1 protein decline in concert with aging (12-15). Yet, the mechanism of age-dependent DNA methylation changes remains unknown. In this study, we found an unexpected connection to the HBP1 transcription factor, which our previous studies had linked to premature senescence (16).HBP1 is a member of the sequence-specific high-mobilitygroup (HMG) family of transcript...

HMGB1 in health and disease

“…WHSC1 is expressed ubiquitously during early development and is involved in chromosomal translocations and histone-lysine N-methyltransferase activity (Hartlerode et al, 2012; Nimura et al, 2009; Pei et al, 2013; Sarai et al, 2013; Yang et al, 2012f). HBP1, as a tumor suppressor protein (Escamilla-Powers et al, 2010; Li et al, 2011b; Zhang et al, 2006), negatively regulates G and S1 phase progression and Wnt signaling (Berasi et al, 2004; Escamilla-Powers et al, 2010; Pan et al, 2013; Sampson et al, 2001; Tevosian et al, 1997; Xiu et al, 2003). BBX functions as a transcription factor and is necessary for cell cycle progression from the G1 to S phase (Stros et al, 2007b).…”

The expression of the tumour suppressor HBP1 is down-regulated by growth factors via the PI3K/PKB/FOXO pathway

“…HBP1 was shown to play a role in cell differentiation through the up-regulation of MPO (myeloperoxidase) in haemopoietic cells [20] or the downregulation of MyoD during terminal differentiation of muscle cells [21] for example. HBP1 has also been implicated in premature senescence induced by an oncogene through the up-regulation of the cell cycle inhibitor p16 INK4A and the down-regulation of DNMT1 (DNA methyltransferase 1) [22][23][24]. The activity of HBP1 is modulated through various mechanisms including its interaction with the retinoblastoma protein pRb and p130 [15,22,25], acetylation by p300/CBP [26] and phosphorylation by the MAPK (mitogen-activated protein kinase) p38 [18].…”

High mobility group box transcription factor 1 (HBP1) from Lampetra japonica affects cell cycle regulation

“…High mobility group (HMG) box‐containing protein 1 (HBP1) is a member of the sequence‐specific HMG family of transcription factors (Pan et al., ; Zhuma et al., ). HBP1 was first identified in the rat brain and was shown to play a critical role in rescuing a potassium channel defect in yeast (Lesage et al., ; Tevosian et al., ).…”