A role of DNA-PK for the metabolic gene regulation in response to insulin.
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.
Wong
Roger H F
RH
Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Chang
Inhwan
I
Hudak
Carolyn S S
CS
Hyun
Suzanne
S
Kwan
Hiu-Yee
HY
Sul
Hei Sook
HS
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000378:metabolism
D007328:Insulin; D012097:Repressor Proteins; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D064429:Fatty Acid Synthases; D051747:DNA-Activated Protein Kinase; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases