Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation

Department of Cellular and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
Science (Impact Factor: 31.48). 09/2010; 329(5996):1201-5. DOI: 10.1126/science.1191241
Source: PubMed

ABSTRACT The mammalian adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase protein complex that is a central regulator of cellular energy homeostasis. However, the mechanisms by which AMPK mediates cellular responses to metabolic stress remain unclear. We found that AMPK activates transcription through direct association with chromatin and phosphorylation of histone H2B at serine 36. AMPK recruitment and H2B Ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which Ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell survival in response to stress. Our results place AMPK-dependent H2B Ser36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.

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    • "One such example is AMPactivated protein kinase (AMPK), a kinase that serves as a metabolic sensor of ATP/AMP ratio [40]. During metabolic stress and in response to low ATP/AMP, AMPK phosphorylates histone H2B on serine 36 that triggers the expression of genes necessary for cell survival and adaptation to metabolic changes [41]. Additionally, modifications of the O-linked N-acetylglucosamine (GlcNAc) type have been reported to occur on histone H2B at serine 112. "
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    • "Interestingly, AMPK also regulates a p53-dependent cell-cycle checkpoint activated by glucose deprivation in cultured cells, thereby limiting growth in energetically unfavorable states (Jones et al., 2005). AMPK also coordinates the expression of stress response genes by localizing to chromatin and phosphorylating histone H2B on serine 36, and this activity facilitates AMPK's effects on gene expression (Bungard et al., 2010). Therefore AMPK executes a number of activities that allow cells to respond decisively and comprehensively to energy shortage. "
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