Abstract:
Excess amounts of histones in the cell induce mitotic chromosome loss and genomic instability, and are therefore detrimental to cell survival. In yeast, excess histones are degraded by the proteasome mediated via the DNA damage response factor Rad53. Histone expression, therefore, is tightly regulated at the protein level. Our understanding of the transcriptional regulation of histone genes is far from complete. In this study, we found that calcineurin inhibitor treatment increased histone protein levels, and that the transcription factor NFATc1 (nuclear factor of activated T cells 1) repressed histone transcription and acts downstream of the calcineurin. We further revealed that NFATc1 binds to the promoter regions of many histone genes and that histone transcription is downregulated in a manner dependent on intracellular calcium levels. Indeed, overexpression of histone H3 markedly inhibited cell proliferation. Taken together, these findings suggest that NFATc1 prevents the detrimental effects of histone H3 accumulation by inhibiting expression of histone at the transcriptional level.
摘要:
细胞中过量的组蛋白诱导有丝分裂染色体丢失和基因组不稳定,因此对细胞存活有害。在酵母中,过量的组蛋白通过DNA损伤反应因子Rad53介导的蛋白酶体降解。组蛋白表达,因此,在蛋白质水平上受到严格调控。我们对组蛋白基因转录调控的理解还很不完整。在这项研究中,我们发现钙调神经磷酸酶抑制剂治疗会增加组蛋白蛋白水平,转录因子NFATc1(活化T细胞的核因子1)抑制组蛋白转录并作用于钙调磷酸酶的下游。我们进一步揭示了NFATc1与许多组蛋白基因的启动子区域结合,并且组蛋白转录以依赖于细胞内钙水平的方式下调。的确,组蛋白H3的过表达显著抑制细胞增殖。一起来看,这些发现表明NFATc1通过在转录水平抑制组蛋白的表达来防止组蛋白H3积累的有害影响。