A Role of DNA-PK for the Metabolic Gene Regulation in Response to Insulin

Roger H.F. Wong, Inhwan Chang, Carolyn S.S. Hudak, Suzanne Hyun, Hiu Yee Kwan, Hei Sook Sul*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

208 Citations (Scopus)

Abstract

Fatty acid synthase (FAS) is a central enzyme in lipogenesis and transcriptionally activated in response to feeding and insulin signaling. The transcription factor USF is required for the activation of FAS transcription, and we show here that USF phosphorylation by DNA-PK, which is dephosphorylated by PP1 in response to feeding, triggers a switch-like mechanism. Under fasting conditions, USF-1 is deacetylated by HDAC9, causing promoter inactivation. In contrast, feeding induces the recruitment of DNA-PK to USF-1 and its phosphorylation, which then allows recruitment of P/CAF, resulting in USF-1 acetylation and FAS promoter activation. DNA break/repair components associated with USF induce transient DNA breaks during FAS activation. In DNA-PK-deficient SCID mice, feeding-induced USF-1 phosphorylation/acetylation, DNA breaks, and FAS activation leading to lipogenesis are impaired, resulting in decreased triglyceride levels. Our study demonstrates that a kinase central to the DNA damage response mediates metabolic gene activation.
Original languageEnglish
Pages (from-to)1056-1072
Number of pages17
JournalCell
Volume136
Issue number6
DOIs
Publication statusPublished - 20 Mar 2009

Scopus Subject Areas

  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • DNA
  • SIGNALING

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