4.8 Article

SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-35182-9

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  1. National Natural Science Foundation of China [31970578, 31872812]
  2. Natural Science Foundation of Hubei Province [2021CFA013, 2019CFA077]
  3. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences [2022ZD01]

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This study reveals the inhibitory effect of H3pT11 on H3K79me3 and uncovers the histone crosstalk regulating autophagy and telomere silencing. It is also discovered that Reb1 recruits the SESAME complex to telomere regions to prevent the invasion of H3K79me3 into heterochromatin, maintaining telomere silencing.
The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere hetero-chromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact mechanism of action for H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

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