Sirtuins in metabolism, DNA repair and cancer

Abstract

The mammalian sirtuin family has attracted tremendous attention over the past few years as stress adaptors and post-translational modifier. They have involved in diverse cellular processes including DNA repair, energy metabolism, and tumorigenesis. Notably, genomic instability and metabolic reprogramming are two of characteristic hallmarks in cancer. In this review, we summarize current knowledge on the functions of sirtuins mainly regarding DNA repair and energy metabolism, and further discuss the implication of sirtuins in cancer specifically by regulating genome integrity and cancer-related metabolism.

Keywords: Cancer; DNA damage; Metabolism; Post-translation modification; Sirtuin.

Fig. 1

Schematic representation of seven mammalian sirtuins. The shaded area represents NAD⁺ - dependent catalytic domain. aa, amino acids

Fig. 2

Overview of sirtuins in glucose metabolism. Selected pathways in nucleus, cytosol and mitochondria are depicted. a Located in cytoplasm, SIRT2 deacetylates the rate-limiting enzyme PEPCK and promotes gluconeogenesis during low nutrient condition. Both SIRT3 and SIRT4 target GDH in mitochondria but their enzymatic activities seem to be opposite. Besides GDH, SIRT4 also reduces PDH activity which converts pyruvate to acetyl CoA. SIRT5 facilitates glycolysis via glycolytic enzyme GAPDH and may disrupt glutamine metabolism through GLS. b In respect to the nuclear sirtuins, both SIRT1 and SIRT6 suppress the transcription factor HIF1α through different manners and subsequently attenuate glycolysis. The reciprocal activation of FOXO1 and its coactivator PGC-1α by SIRT1 reinforces the gluconeogenic transcription. By contrast, SIRT6 down-regulates PGC-1α and suppresses hepatic glucose production. PEPCK,phosphoenolpyruvate carboxykinase; GDH,glutamate dehydrogenase; PDH,pyruvate dehydrogenase; GAPDH,glyceraldehyde phosphate dehydrogenase; GLS,glutaminase; PGC-1α,Peroxisome proliferator-activated receptor gamma coactivator 1 α; FOXO1,forkhead box protein O1

Fig. 3

Overview of sirtuins in lipid metabolism. Selected pathways in nucleus, cytosol and mitochondria are depicted. a Activating LCAD, a key enzyme in long-chain fatty acids oxidation, SIRT3 increases β-oxidation in hepatocytes and skeletal muscle. Both SIRT3 and SIRT5 promotes ketogenesis via HMGCS2 in liver. In cytoplasm, SIRT2 deacetylates ACLY and deters lipid synthesis. In contrast to SIRT3, SIRT4 inhibits MCD and contributes to increased malonyl CoA,which suppresses the fatty acid translocator CAT-1 and shuts down entery of fatty acid for β-oxidation. b SIRT1 and SIRT6 reduce the activity of nuclear hormone receptor PPARγand lead to decreased adipogenesis. SIRT1 also destabilizes SREBP1 and transcriptionally represses lipogenesis. Besides the negative regulation, SIRT1 boosts fatty acid oxidation by enhancing PPARα and its coactivator PGC1α. LCAD, long chain acyl CoA dehydrogenase; HMGCS2,3-hydroxy-3-methylglutaryl CoA synthase 2; ACLY,ATP citrate lyase; MCD,malonyl CoA decarboxylase; CAT-1,carnitine acyl transferase-1; SREBP1,sterol regulatory element binding protein 1

Fig. 4

Nuclear sirtuins regulate genomic stability and their roles in the DDR are summarized. SIRT1 is implicated in diverse DNA repair pathways. SIRT1 promotes HR DNA repair by deacetylating WRN, a DNA helicase. It also regulates NHEJ and NER through Ku70 and XPA and XPC after genotoxic stimuli. Like SIRT1, SIRT6 modulates DNA repair pathways at multiple layers. SIRT6 affects BER in a PARP1-depdendent manner and recruits DNA-PK to promote NHEJ. It interacts with two major BER enzymes MYH and APE1 as well. Most recent study uncovered SIRT7 induce NHEJ by recruiting repair factor 53BP1. XPA and XPC, xeroderma pigmentosum A and C; APE1,Apurinic/apyrimidinic endonuclease 1; DNA-PK,DNA-dependent protein kinase