Cooperation of DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops

Werner syndrome is an inherited human progeriod syndrome caused by mutations in the gene encoding the Werner Syndrome protein, WRN. It has both 3'-5' DNA helicase and exonuclease activities, and is suggested to have roles in many aspects of DNA metabolism, including DNA repair and telomere maintenance. The DNA-PK complex also functions in both DNA double strand break repair and telomere maintenance. Interaction between WRN and the DNA-PK complex has been reported in DNA double strand break repair, but their possible cooperation at telomeres has not been reported. This study analyzes thein vitro and in vivo interaction at the telomere between WRN and DNA-PKcs, the catalytic subunit of DNA-PK. The results show that DNA-PKcs selectively stimulates WRN helicase but not WRN exonuclease in vitro, affecting that WRN helicase unwinds and promotes the release of the full-length invading strand of a telomere D-loop model substrate. In addition, the length of telomeric G-tails decreases in DNA-PKcs knockdown cells, and this phenotype is reversed by overexpression of WRN helicase. These results suggest that WRN and DNA-PKcs may cooperatively prevent G-tail shortening in vivo

What does the local structure of a planar graph tell us about its global structure?

The local k-neighborhood of a vertex v in an unweighted graph G = (V,E) with vertex set V and edge set E is the subgraph induced by all vertices of distance at most k from v. The rooted k-neighborhood of v is also called a k-disk around vertex v. If a graph has maximum degree bounded by a constant d, and k is also constant, the number of isomorphism classes of k-disks is constant as well. We can describe the local structure of a bounded-degree graph G by counting the number of isomorphic copies in G of each possible k-disk. We can summarize this information in form of a vector that has an entry for each isomorphism class of k-disks. The value of the entry is the number of isomorphic copies of the corresponding k-disk in G. We call this vector frequency vector of k-disks. If we only know this vector, what does it tell us about the structure of G? In this paper we will survey a series of papers in the area of Property Testing that leads to the following result (stated informally): There is a k = k(ε,d) such that for any planar graph G its local structure (described by the frequency vector of k-disks) determines G up to insertion and deletion of at most εd n edges (and relabelling of vertices)

Measurement of the cosmic-ray antiproton spectrum at solar minimum with a long-duration balloon flight over Antarctica

The energy spectrum of cosmic-ray antiprotons from 0.17 to 3.5 GeV has been measured using 7886 antiprotons detected by BESS-Polar II during a long-duration flight over Antarctica near solar minimum in December 2007 and January 2008. This shows good consistency with secondary antiproton calculations. Cosmologically primary antiprotons have been investigated by comparing measured and calculated antiproton spectra. BESS-Polar II data show no evidence of primary antiprotons from evaporation of primordial black holes.Comment: 4 pages, 4 figures, submitted to Physical Review Letter

A comparative study of far-field tsunami amplitudes and ocean-wide propagation properties: Insight from major trans-Pacific tsunamis of 2010-2015

Copyright © The Author(s) 2018. We studied ocean-wide propagation properties of four recent trans-Pacific tsunamis based on deep-ocean measurements across the Pacific Ocean. First, we analyzed and simulated the 16 September 2015 tsunami generated by the Illapel (Chile) earthquake (Mw 8.4) and compared its ocean-wide propagation with those of three other events: the 2014 Iquique (Mw 8.2), 2010 Maule (Mw 8.8) and 2011 Tohoku (Mw 9.0). The Illapel and Maule tsunami sources are located close to each other and we reconstructed the source spectrum of the larger (i.e. Maule) tsunami by applying spectral deconvolution using the smaller (i.e. Illapel) tsunami as the empirical Green's function. The initial negative phase was found for all four events with durations of 8–29 (Iquique), 20–35 (Illapel), 22–70 (Maule) and 40–79 (Tohoku) min, with the maximum amplitudes of 0.11–0.26, 0.4–0.7, 0.5–2.9 and 1.9–2.5 cm, and the amplitude ratios to the first elevation phases of 20–40 per cent, 22–41 per cent, 29–61 per cent and 12–67 per cent, respectively. Unlike other studies, our results revealed that the duration ({D_{ini}}$ $) and amplitude ({A_{ini}}$$) of the initial negative phase are directly proportional to the earthquake magnitude ({M_w}$ $) with equations: {M_w} = \;6.129 + 1.629\;{\rm{log}}( {{D_{ini}}} )$$ and {M_w} = \;8.676 + 0.706\;{\rm{log}}( {{A_{ini}}} )$ $. No relationships were observed between these parameters (i.e. {D_{ini}}$$ and {A_{ini}}$ $) and distance from the source. The amplitudes of far-field DART waves do not vary with distance or strike angle, and depend only on the {M_w}$$. The average far-field deep-ocean amplitudes ({A_{tsu}}$ $) for the Iquique, Illapel, Maule and Tohoku tsunamis were 0.9, 1.7, 6.0 and 15.0 cm, respectively, yielding the equation: {M_w} = \;8.245 + 0.665\;{\rm{log}}( {{A_{tsu}}} )$$.Brunel Research Initiative and Enterprise Fun

Structure and mechanism of human DNA polymerase η

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Pol eta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol eta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol eta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol eta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol eta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol eta in replicating through D loop and DNA fragile sites

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