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The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR in human and mouse cells. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair in humans and mice.

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases., eLife digest As cells live and divide, their genetic material gets damaged. The DNA damage response is a network of proteins that monitor, recognize and fix the damage, which is also called DNA lesions. For example, an enzyme called ATM senses when DNA is broken and then begins a process that will get it repaired, while another enzyme known as SIRT6 participates in the actual mending process. When organisms get older, the repair machinery becomes less efficient, and the number of DNA lesions and errors increases. The accumulation of DNA damage may cause the ‘symptoms’ of old age – from cancer, to wrinkles and the slowing down of the body’s chemical processes. In fact, individuals with defective ATMs (who thus struggle to repair their DNA) age abnormally fast; conversely, SIRT6 promotes longevity. If declining repair mechanisms cause aging, would boosting the DNA damage response slow down this process? Chloroquine is a drug used to combat malaria, but it can also enhance the activity of ATM without damaging DNA. Qian, Liu et al. show that chloroquine helps cells remove broken DNA and keep dividing for longer. In animals, the drug increases the lifespan of worms and prolongs the lives of mice who have mutations that make them age quicker. Qian, Liu et al. also demonstrate that ATM works by chemically altering the pro-longevity enzyme SIRT6. These changes make SIRT6 more stable, and keep it safe from cellular processes that destroy it. In addition, mice that are genetically engineered to lack ATM can survive for longer if they also produce extra SIRT6. These experiments show that enhancing the DNA damage response can slow down aging, thus linking the DNA repair machinery to longevity. Progeria is a group of rare genetic conditions with inefficient DNA repair; people with progeria age fast and die young. The results by Qian, Liu et al., if confirmed in humans, could provide a new way of treating these diseases.