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  • br The important role of DNA PK in

    2020-08-03


    The important role of DNA-PK in metabolic gene regulation To meet the constant energy requirement in the face of highly variable food supply, mammals employ intricate and precise mechanisms for energy storage. When total energy intake is in excess of energy expenditure (such as after a meal), excess carbohydrates are converted to fatty acids (de novo lipogenesis). Excess fatty acids are then converted to triacylglycerols to be stored in adipose tissue and released as oxidative fuels for other tissues during times of energy need (such as fasting and exercise). In sustaining the balance between energy excess and energy deficiency, the process of lipogenesis is tightly controlled by nutritional and hormonal conditions [94]. PKC412 mg Thus, enzymes involved in fatty PKC412 mg and fat synthesis are tightly and coordinately regulated during fasting/feeding: The expression of the lipogenic enzymes is very low in fasting due to the increase in glucagon/cAMP levels. Conversely, in the fed condition, especially after a high carbohydrate meal, the expression of these enzymes is drastically upregulated and accompanied by an increase in insulin secretion [94], [95], [96]. Fatty acid synthase (FAS), a central lipogenic enzyme, plays a crucial role in de novo lipogenesis by catalyzing all of the seven reactions involved in fatty acid synthesis. Upstream Stimulatory Factor (USF) binding to the −65 E-box is required for the regulation of FAS promoter activity in fasting/feeding [97], [98]. DNA-PK are identified as a USF-interacting protein [99]. In response to feeding/insulin, the transient double-stranded DNA breaks occurred during the transcriptional activation of FAS promoter, which might recruit DNA-PK to the DSB sites near FAS promoter. Moreover, DNA-PK has recently been shown to be required for USF-1 complex assembly and recruitment of its other interacting proteins. Upon feeding, transient DSB-recruited DNA-PK, which is dephosphorylated/activated by PP1, and the activated DNA-PK mediates feeding-dependent Ser 262 phosphorylation of USF-1, which governs interaction between USF-1 and its partners. USF-1 and SREBP-1 (SRE binding protein), another transcription factor in lipogenic promoters, directly interact for FAS promoter activation [100], [101], SREBP-1 interacts more efficiently with the phosphorylated USF-1, which, in turn, enhances the interaction between USF-1 and DNA-PK, leading to USF-1 phosphorylation, an indication of positive feed-forward regulation. In addition, DNA-PK-catalyzed phosphorylation of USF-1 allows P/CAF recruitment and subsequent Lys 237 acetylation of USF-1. As a result, FAS transcription is activated by USF-1 (Fig. 2). Thus, the transcriptional activation of lipogenic genes is impaired in DNA-PK-deficient SCID mice. Of course, the FAS promoter activation is in a reversible manner in response to nutritional status. USF-1 recruits histone deacetylasse 9 (HDAC9) in the fasted state, which deacetylates USF-1 to repress transcription despite its binding to the E box (Fig. 2). In brief, DNA-PK plays an important role in the USF-1-mediated transcriptional regulation of lipogenic genes during fasting/feeding.