SIRT6 is a DNA Double-Strand Break Sensor

Onn, Lior; Portillo, Miguel; Ilić, Stefan; Cleitman, Gal; Stein, Daniel; Kaluski, Shai; Shirat, Ido; Slobodnik, Zeev; Einav, Monica; Erdel, Fabian; Akabayov, Barak; Toiber, Debra

doi:10.1101/765172

Cited by 23 publications

(35 citation statements)

References 57 publications

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“…Tau-174Ac is translocated into the nucleus upon DNA damage SIRT6 is critical to ensure DNA repair (Mostoslavsky et al, 2006;Toiber et al, 2013). We have recently shown that it acts as a double-strand break (DSB) sensor (Onn et al, 2020) and prevents genomic instability. We have previously established a connection among DSB signaling, Tau stability and its accumulation through GSK3 activation, and Tau phosphorylation (Kaluski et al, 2017).…”

Section: Sirt6 Regulates Tau Stability and Nuclear Location Through The Deacetylation Of Residue 174mentioning

confidence: 99%

“…Our results showed that either DNA damage or SIRT6 deletion increased CBP levels in the nucleus and cytoplasm (Figures 4 and S4). SIRT6-KO cells are deficient in their ability to repair DNA, and CBP is a key player in DSB repair (Dutto et al, 2018;Mostoslavsky et al, 2006;Onn et al, 2020;Piekna-Przybylska et al, 2016;Toiber et al, 2013); thus, its overexpression might be the outcome of persistent DNA damage signaling and an important component of the cellular efforts to mitigate DNA damage. Our results show that preventing CBP activity can also ameliorate Tau accumulation and nuclear localization.…”

Section: Sirt6 Regulates Tau Stability and Nuclear Location Through The Deacetylation Of Residue 174mentioning

confidence: 99%

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SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis

et al. 2021

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Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau posttranslational modifications such as phosphorylation and acetylation are increased in neurodegeneration.Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, synthesis, and energy production. Concomitantly, Alzheimer's disease (AD) case subjects show increased nucleolin and a decrease in SIRT6 levels. AD case subjects present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD case subjects is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation, and nucleolar dysfunction.

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Section: Sirt6 Regulates Tau Stability and Nuclear Location Through The Deacetylation Of Residue 174mentioning

confidence: 99%

Section: Sirt6 Regulates Tau Stability and Nuclear Location Through The Deacetylation Of Residue 174mentioning

confidence: 99%

SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis

et al. 2021

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“…1 , bottom), including Ercc6 m/m Xpa −/− , Ercc1 −/− and Ercc1 −/d7 (mean r s = 0.24). Sirt6 −/− also showed similarity with Ercc1 −/d7 and Ercc6 m/m Xpa −/− , which may be explained by the recently discovered function of Sirt6 as a DNA strand break sensor and activator of the DNA damage response ( Onn et al, 2020 ). The only statistically significant negative correlation we found was between Tert and Sirt6 knockout mice.…”

Section: Resultsmentioning

confidence: 74%

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

Fuentealba

Fabian

Dönertaş

et al. 2021

Mechanisms of Ageing and Development

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Highlights Transcriptomic changes are more similar within mutant mice that show either lengthened or shortened lifespan. The major transcriptomic differences between long- and short-lived mice are in genes controlling mitochondrial metabolism. Gene expression changes in short-lived, progeroid, mutant mice resemble those seen during normal ageing.

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“…The recent studies by Onn et al. 221 found SIRT6 to share a role with PARP1 as a DNA double-strand break sensor, a finding which, in conjunction with the enzyme’s function in the recruitment of proteins of the homologous recombination and non-homologous end joining pathways, may contribute to increased SIRT6 activity and efficiency of DSB repair in long-lived species. 222 To this end, SIRT6-deficient cynomolgus monkeys ( Macaca fascicularis ) displayed severe developmental retardation and dramatically reduced survival, emphasizing the protein’s role in primate development.…”

Section: Nad Functions As Substratementioning

confidence: 99%

NAD metabolism in aging and cancer

Kincaid

Berger

2020

Exp Biol Med (Maywood)

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NAD+ and its derivatives NADH, NADP+, and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed. Impact statement NAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.

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SIRT6 is a DNA Double-Strand Break Sensor

Cited by 23 publications

References 57 publications

SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis

SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

NAD metabolism in aging and cancer

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