Beyond Making Ends Meet: DNA-PK, Metabolism, and Aging
2017; Cell Press; Volume: 25; Issue: 5 Linguagem: Inglês
10.1016/j.cmet.2017.04.022
ISSN1932-7420
AutoresXiao Tian, Andrei Seluanov, Vera Gorbunova,
Tópico(s)CRISPR and Genetic Engineering
ResumoDNA-dependent protein kinase (DNA-PK), a central player in DNA double-strand break (DSB) repair, shows emerging roles in metabolic regulation. In this issue of Cell Metabolism, Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar elucidate a molecular mechanism whereby DNA-PK negatively regulates AMPK, contributing to metabolic and fitness decline during aging. DNA-dependent protein kinase (DNA-PK), a central player in DNA double-strand break (DSB) repair, shows emerging roles in metabolic regulation. In this issue of Cell Metabolism, Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar elucidate a molecular mechanism whereby DNA-PK negatively regulates AMPK, contributing to metabolic and fitness decline during aging. DNA-dependent protein kinase (DNA-PK) plays key roles in DNA double-strand break (DSB) repair and V(D)J recombination. DNA-PK is a trimeric complex, composed of DNA-PK catalytic subunit (DNA-PKcs) and DNA binding subunits, Ku70 and Ku80. Ku70 and Ku80 bind to DNA breaks and activate DNA-PKcs kinase activity to initiate DNA repair by nonhomologous end joining (NHEJ) pathway. Knocking out any of the three components in mice causes premature aging and immunodeficiency. Emerging evidence links DNA-PK to functions beyond DSB repair, specifically metabolic regulation. DNA-PK was shown to transcriptionally upregulate genes involved in lipogenesis in response to feeding and insulin signaling (Wong et al., 2009Wong R.H. Chang I. Hudak C.S. Hyun S. Kwan H.Y. Sul H.S. Cell. 2009; 136: 1056-1072Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). In the case of glucose deprivation, DNA-PK was shown to promote the activation of AMP-activated protein kinase (AMPK), a crucial energy sensor, to restore energy balance (Amatya et al., 2012Amatya P.N. Kim H.B. Park S.J. Youn C.K. Hyun J.W. Chang I.Y. Lee J.H. You H.J. Biochim. Biophys. Acta. 2012; 1823: 2099-2108Crossref PubMed Scopus (21) Google Scholar). In this issue of Cell Metabolism, Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar demonstrate that during aging in skeletal muscle, increased DSBs lead to constitutive activation of DNA-PK, which in turn downregulates AMPK and promotes functional decline. The mechanism for this unexpected age-promoting effect of DNA-PK involves HSP90α, whose function is to facilitate AMPK folding. DNA-PK phosphorylates HSP90α and decreases its ability to bind AMPK. Decreased AMPK activity in aged skeletal muscle leads to decline of mitochondrial function and reduced fitness. Remarkably, Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar showed that age-associated metabolic decline can be rescued by inhibiting DNA-PK. SCID mice that carry mutation in DNA-PK as well as a tissue-specific knockout of DNA-PKcs increased running speed and endurance of aged animals. Chemical inhibitor of DNA-PK, NU7441, achieved a similar effect. Importantly, the rescue effect was dependent on AMPK, as no beneficial effect of inhibiting DNA-PK was observed in AMPK knockout animals. Dysregulated AMPK is associated with multiple age-related diseases, including type 2 diabetes, cardiovascular diseases, and cancer. Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar found that administration of the DNA-PK inhibitor protected the animals from obesity and type 2 diabetes by activating multiple AMPK targets. These findings are of great importance to the aging field because they uncover a novel mechanism by which accumulation of DNA damage leads to functional decline during aging. The role of DNA damage in aging has been a subject of debate (Campisi and Vijg, 2009Campisi J. Vijg J. J. Gerontol. A Biol. Sci. Med. Sci. 2009; 64: 175-178Crossref PubMed Scopus (80) Google Scholar). Clearly, artificially increased levels of DNA damage accelerate the aging process; however, whether the basal levels of damage drive age-related functional decline had been unclear. One consequence of DNA damage is accumulation of mutations, which may also impact the functionality of normal tissues (Vijg, 2014Vijg J. Curr. Opin. Genet. Dev. 2014; 26: 141-149Crossref PubMed Scopus (92) Google Scholar) and ultimately lead to cancer. Furthermore, DNA damage may trigger cellular senescence, which contributes to age-related functional decline (Baar et al., 2017Baar M.P. Brandt R.M. Putavet D.A. Klein J.D. Derks K.W. Bourgeois B.R. Stryeck S. Rijksen Y. van Willigenburg H. Feijtel D.A. et al.Cell. 2017; 169: 132-147.e16Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar). Now, Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar added a new mechanism whereby DNA damage leads to a signaling and metabolic imbalance via inhibition of AMPK. The latter mechanism works in skeletal muscle, but not in the lung. It would be important to test other tissues to understand how universal these effects are. For instance, liver plays a key role in metabolic regulation, and understanding whether DNA damage results in AMPK inhibition in the liver is of great importance. The most remarkable observation made by Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar is that a small molecule inhibitor of DNA-PK improved fitness of the aged mice. Does this mean we should all start taking DNA-PK inhibitors? Perhaps not. Silencing the DNA damage signal to improve cellular metabolism is akin to treating a symptom without addressing the underlying disease. If you have appendicitis, taking a painkiller may let you come to work in the morning, but you still must go to the hospital to receive life-saving treatment. In the case of DNA-PK, the underlying cause is DNA damage and DNA-PK enzyme becomes activated to promote repair of this damage. If the damage is not repaired it may lead to cancer and further functional decline. In this regard, human lifespan is dramatically longer than mouse lifespan while cancer causing mutational events need time to accumulate. A temporary relief from DNA-PK may serve the mouse well since an aged mouse only has a few months left to live. In contrast, aged humans may have a decade or two of life ahead of them, and gaining some improvement in muscle performance while increasing the risk of cancer may not be the best solution. 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., 2014Vaidya A. Mao Z. Tian X. Spencer B. Seluanov A. Gorbunova V. PLoS Genet. 2014; 10: e1004511Crossref PubMed Scopus (66) Google Scholar). 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., 2012Mao Z. Tian X. Van Meter M. Ke Z. Gorbunova V. Seluanov A. Proc. Natl. Acad. Sci. USA. 2012; 109: 11800-11805Crossref PubMed Scopus (131) Google Scholar). Interventions aimed at stimulating SIRT6 with small molecule activators and/or increasing cellular NAD+ pools (Zhang et al., 2016Zhang H. Ryu D. Wu Y. Gariani K. Wang X. Luan P. D'Amico D. Ropelle E.R. Lutolf M.P. Aebersold R. et al.Science. 2016; 352: 1436-1443Crossref PubMed Scopus (700) Google Scholar) would reduce DNA damage and improve metabolic health in aged tissues (Figure 1). A puzzling question arising from this study is the physiological function of HSP90α phosphorylation. If such a modification had evolved it must be beneficial under certain conditions. The same agents that damage DNA can also damage proteins. Therefore, inactivating protein chaperones in response to DNA damage does not seem to be advantageous for the cell. It would be interesting to test whether the specificity of HSP90α changes following phosphorylation by DNA-PK, and it begins to facilitate folding of a new group of proteins rather than becoming inactive altogether. In summary, the work by Park et al., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar 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., 2017Park S.-J. Gavrilova O. Brown A.L. Soto J.E. Bremner S. Kim J. Yang S. Um J.-H. Koch L.G. Britton S.L. et al.Cell Metab. 2017; 25 (this issue): 1135-1146Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar 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. DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During AgingPark et al.Cell MetabolismMay 02, 2017In BriefPark et al. show that metabolic and fitness decline with age is mediated by a genetic program, not simply "wear and tear." Increased DNA breaks in aged skeletal muscle induce DNA-PK phosphorylation of HSP90α, which decreases AMPK activity and mitochondrial function. Inhibiting DNA-PK ameliorates obesity, T2DM, and physical decline. Full-Text PDF Open Archive
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