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:10.7554/elife.51636

Cited by 110 publications

(99 citation statements)

References 66 publications

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“…Among shortlived models, the highest correlation was observed between interventions in the DNA repair system (Figure 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: Similarities and Differences In Patterns Of Transcriptionalsupporting

confidence: 53%

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. 2020

Preprint

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Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes and also the whole transcriptome, we observed that the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes.

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Section: Similarities and Differences In Patterns Of Transcriptionalsupporting

confidence: 53%

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. 2020

Preprint

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“…Furthermore, as SIRT6 rapidly localizes to sites of DNA damage, the CTD may play a role in binding damaged DNA or initiating proper cellular responses to DNA damage. In support, a recent report reveals that ectopic GFP-SIRT6 localizes to damaged DNA independent of other known DNA repair proteins 47 . Mutagenesis of predicted DNA-binding residues in the folded core of SIRT6 disrupted in vitro DNA binding to a minor extent, albeit at unknown protein concentrations and with unknown protein stability 47 .…”

Section: Discussionmentioning

confidence: 57%

Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6

et al. 2020

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The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules associate with the acidic patch on the nucleosome, we find that the intrinsically disordered SIRT6 C-terminus promotes binding at the higher affinity site through recognition of nucleosomal DNA. Together, multivalent interactions couple productive binding to efficient deacetylation of histones on endogenous chromatin. Unique among histone deacetylases, SIRT6 possesses the intrinsic capacity to tightly interact with nucleosomes for efficient activity.

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“…Repair of such damage is essential for DNA replication and, of particular importance for long-lived post-mitotic neuronal cells, transcription [386][387][388]. Proteins encoded by Bmi1, Dgcr8, Dicer1, Elp1, Ercc1, Ercc6, Msi1, Sirt6, Top2b, Ubb, and Uchl3 are known to participate in the DNA damage response [387,[389][390][391][392][393][394][395][396][397][398], some in transcription-coupled DNA repair. For example, BMI1 represses transcription at sites of UV-induced DNA damage to allow repair [389]; ELP1 is a required component of the Elongator complex [399], which couples RNA polymerase II to an alkyladenine glycosylase that initiates base excision repair [392]; ERCC6 promotes DSB repair in actively transcribed regions by displacing RNA polymerase from the lesion site [387], and DGCR8 interacts with both RNA polymerase II and ERCC6 to mediate transcription-coupled nucleotide excision repair of UV-induced DNA lesions [390].…”

Section: Category 10: Dna Repair Rna Biogenesis and Protein Modificmentioning

confidence: 99%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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SIRT6 is a DNA double-strand break sensor

Cited by 110 publications

References 66 publications

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

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

Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

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