Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

Shihao Zhang, Xilan Yu, Yuan Zhang, Xiangyan Xue, Qi Yu, Zitong Zha, Madelaine Gogol, Jerry L. Workman and Shanshan Li ()
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Shihao Zhang: Hubei University
Xilan Yu: Hubei University
Yuan Zhang: Hubei University
Xiangyan Xue: Hubei University
Qi Yu: Hubei University
Zitong Zha: Nanchang University
Madelaine Gogol: Stowers Institute for Medical Research
Jerry L. Workman: Stowers Institute for Medical Research
Shanshan Li: Hubei University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identify a function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAME-catalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.

Date: 2021
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DOI: 10.1038/s41467-020-20711-1

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