SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair

The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor

The Distribution of Basaltic Asteroids in the Main Belt

We present the observational results of a survey designed to target and detect asteroids whose colors are similar to those of Vesta family members and thus may be considered as candidates for having a basaltic composition. Fifty basaltic candidates were selected with orbital elements that lie outside of the Vesta dynamical family. Optical and near-infrared spectra were used to assign a taxonomic type to 11 of the 50 candidates. Ten of these were spectroscopically confirmed as V-type asteroids, suggesting that most of the candidates are basaltic and can be used to constrain the distribution of basaltic material in the Main Belt. Using our catalog of V-type candidates and the success rate of the survey, we calculate unbiased size-frequency and semi-major axis distributions of V-type asteroids. These distributions, in addition to an estimate for the total mass of basaltic material, suggest that Vesta was the predominant contributor to the basaltic asteroid inventory of the Main Belt, however scattered planetesimals from the inner Solar System (a < 2.0 AU) and other partially/fully differentiated bodies likely contributed to this inventory. In particular, we infer the presence of basaltic fragments in the vicinity of asteroid 15 Eunomia, which may be derived from a differentiated parent body in the middle Main Belt (2.5 < a < 2.8). We find no asteroidal evidence for a large number of previously undiscovered basaltic asteroids, which agrees with previous theories suggesting that basaltic fragments from the ~100 differentiated parent bodies represented in meteorite collections have been "battered to bits" [Burbine, T.H., Meibom, A., Binzel, R.P., 1996. Mantle material in the Main Belt: Battered to bits? Met. & Planet. Sci. 31, 607].Comment: 67 pages, 11 figures, accepted to Icaru

Contribution of Transcription Factor Binding Site Motif Variants to Condition-Specific Gene Expression Patterns in Budding Yeast

It is now experimentally well known that variant sequences of a cis transcription factor binding site motif can contribute to differential regulation of genes. We characterize the relationship between motif variants and gene expression by analyzing expression microarray data and binding site predictions. To accomplish this, we statistically detect motif variants with effects that differ among environments. Such environmental specificity may be due to either affinity differences between variants or, more likely, differential interactions of TFs bound to these variants with cofactors, and with differential presence of cofactors across environments. We examine conservation of functional variants across four Saccharomyces species, and find that about a third of transcription factors have target genes that are differentially expressed in a condition-specific manner that is correlated with the nucleotide at variant motif positions. We find good correspondence between our results and some cases in the experimental literature (Reb1, Sum1, Mcm1, and Rap1). These results and growing consensus in the literature indicates that motif variants may often be functionally distinct, that this may be observed in genomic data, and that variants play an important role in condition-specific gene regulation

Muscle cramping during exercise : causes, solutions and questions remaining

Muscle cramp is a temporary but intense and painful involuntary contraction of skeletal muscle that can occur in many different situations. The causes of, and cures for, the cramps that occur during or soon after exercise remain uncertain, although there is evidence that some cases may be associated with disturbances of water and salt balance, while others appear to involve sustained abnormal spinal reflex activity secondary to fatigue of the affected muscles. Evidence in favour of a role for dyshydration comes largely from medical records obtained in large industrial settings, although it is supported by one large-scale intervention trial and by field trials involving small numbers of athletes. Cramp is notoriously unpredictable, making laboratory studies difficult, but experimental models involving electrical stimulation or intense voluntary contractions of small muscles held in a shortened position can induce cramp in many, although not all, individuals. These studies show that dehydration has no effect on the stimulation frequency required to initiate cramping and confirm a role for spinal pathways, but their relevance to the spontaneous cramps that occur during exercise is questionable. There is a long history of folk remedies for treatment or prevention of cramps; some may reduce the likelihood of some forms of cramping and reduce its intensity and duration, but none are consistently effective. It seems likely that there are different types of cramp that are initiated by different mechanisms; if this is the case, the search for a single strategy for prevention or treatment is unlikely to succeed.Publisher PDFPeer reviewe

SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin.

The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome