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  • Then what is the solution to

    2019-09-23

    Then what is the solution to tackle DNA damage-induced metabolic decline? The culprit here may be not DNA damage signaling per se, but rather the persistent activation of the DNA damage signaling pathways due to age-related accumulation of DNA damage. DNA repair, including repair by NHEJ, is an essential process to maintain cellular genetic material, but NHEJ efficiency and accuracy decline with age (Vaidya et al., 2014). Counteracting age-related decline in DNA repair would provide us with youthful DNA repair machinery and prevent age-related accumulation of DNA damage with all its consequences, including metabolic dysregulation. Overexpressing SIRT6, a member of the sirtuin family, was sufficient to rescue senescence-associated decline in DNA repair (Mao et al., 2012). Interventions aimed at stimulating SIRT6 with small molecule activators and/or increasing cellular NAD+ pools (Zhang et al., 2016) would reduce DNA damage and improve metabolic health in aged tissues (Figure 1). In summary, the work by Park et al. (2017) provides a strong evidence for the role of DNA damage in normal aging. By uncovering the link between activation of DNA damage and metabolic decline Park et al. (2017) demonstrate that the consequences of unrepaired DNA breaks go beyond mutations but also affect the energetic balance of the tissue. This study will spur more interest in identifying interventions that improve DNA repair and dissecting the metabolic aspect of aging caused by genomic instability and developing targeted anti-aging therapies.
    Introduction DNA is the main target of many conventional anticancer agents and therefore the inhibition of DNA repair is an attractive approach to chemosensitisation. DNA double-strand breaks are the most lethal type of DNA damage and therefore two major pathways have evolved to repair these DNA lesions; homologous Torin 1 (HR) and non-homologous end-joining (NHEJ). DNA-PK is a serine/threonine protein kinase and is a member of the phosphatidylinositol 3-kinase like kinase (PIKK) family. DNA-PK is essential for the NHEJ repair pathway [1], and has also been implicated in HR [2], H2AX phosphorylation [3], metabolic gene regulation [4], and in the inflammatory response through interactions with NFκB [5]. NU7441 (8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one, Fig. 1(a)) is a potent ATP-competitive DNA-PK inhibitor (IC50=14nM) developed from the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 [6]. NU7441 has been shown to increase sensitivity to radiation and topoisomerase II poisons, and increase etoposide-induced tumour growth delay in mice bearing SW620 xenografts [7]. The mechanism by which this occurs has previously been demonstrated that NU7441 retards the repair of both IR- and etoposide-induced DNA double strand breaks and inhibits homologous recombination in a DNA-PK dependent manner [7], [8]. NU7441 is around 20-fold more selective for cellular DNA-PK over PI3K inhibition [8]. NU7742 (8-dibenzothiophen-4-yl-2-piperidin-1-yl-chromen-4-one, Fig. 1(b)) is an inactive derivative of NU7441 (IC50>10μM) in which the morpholine oxygen has been replaced with a methylene group, resulting in the loss of sensitisation of cells to DNA-damaging agents [9]. The introduction of a methyl substituent at the 7-position of the chromen-4-one ring generated atropisomers DRN1 (DNA-PK IC50=2nM) and DRN2 (DNA-PK IC50=7μM) (Fig. 1(c)). As expected and due to restricted rotation between the chromen-4-one and dibenzothiophene rings, the DNA-PK inhibitory activity resides exclusively in Torin 1 the laevorotatory enantiomer DRN1 [10]. MDR1/P-glycoprotein (the product of the ABCB1/MDR1 gene) was the first member of the (ATP)-binding cassette (ABC) superfamily of transmembrane transporters to be cloned, and is known to play a significant role in the multidrug-resistance (MDR) phenotype in cancer cells [11]. MDR1 is a 170kDa protein located in the apical membrane of many cell types which acts as a drug efflux transporter in the liver, kidneys, gastrointestinal tract, and multiple blood barriers including the blood–brain and the blood–placental barriers [12], [13]. MDR1 is known to play a role in conferring resistance to a number of anticancer agents, including the vinca alkaloids, taxanes and anthracyclines [14].