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CEO Secrets: 'Spend more on staff than clients'

BBC News

Jamie Bolding is founder of Jungle Creations, the social media company behind strands including Viral Thread and Twisted Food. He shares the business advice he wishes he had had when he started out for our CEO Secrets series, from his company's new offices in east London. You can watch our live Facebook interview with him here. Shhh! Get all the #CEOSecrets on our website here and watch this video explaining the series. To keep up to date with the CEO Secrets series and go behind the scenes, follow series producer Dougal Shaw on Twitter and Facebook.


The secret life of histones

Science

Histone proteins are the ubiquitous organizers of all eukaryotic genomes ([ 1 ][1]). Two each of the histones H2A, H2B, H3, and H4 form a disk-shaped assembly around which 147 base pairs (bp) of DNA are tightly coiled. Hundreds of thousands of these connected nucleosomes wrap up further to form chromosomes. The substantial sequence conservation between eukaryotic histones and the presence of simple histones in archaea (the presumed ancestors of all eukaryotes) suggest an ancient evolutionary origin of this type of genome organization ([ 2 ][2]). Certainly, there was no reason to believe that histones had any other function, let alone enzymatic activity. On page 59 of this issue, Attar et al. ([ 3 ][3]) describe the unexpected discovery that histone H3 has copper reductase activity in yeast (and likely in all) cells, suggesting that histones may have evolved to adapt to oxygenated life rather than for DNA compaction. Copper is an essential element for all living organisms because it is a cofactor for many enzymatic reactions. Copper is a required component of the energy-generating enzyme cytochrome c oxidase and the detoxifying enzyme superoxide dismutase (which renders superoxide radicals that causes many types of cell damage harmless), thus allowing for safe respiration in oxygen-utilizing organisms. As an enzymatic cofactor, copper cycles through its two readily accessible oxidation states, Cu+ (cuprous) and Cu2+ (cupric). However, copper mostly occurs in nature as Cu2+, which is toxic because it can readily oxidize essential thiols or ascorbic acid (vitamin C) and thus obliterate their functions. Thus, the adaptation of life from an anaerobic to an oxygenated environment (which happened in the same time frame as eukaryogenesis) required a mechanism for maintaining Cu+ inside cells. Typical Cu binding sites in proteins bind one to four ions in oxidation states ranging from Cu+ to Cu3+, coordinated most often by histidine and cysteine residues as well as water ([ 4 ][4]). Thus, the conserved occurrence of two Cys-His pairs in the histone H3-H3 four-helix bundle structure that occurs in all eukaryotic organisms except for baker's yeast, Saccharomyces cerevisiae , piqued the interest of Attar et al. , especially given the previous proposal that these Cys-His pairs could bind metal ions ([ 5 ][5]). The Cys-His pairs are part of the dimerization interface that holds together the H3-H4 tetramer (comprising two H3 and H4 dimers), which organizes the central ∼80 bp of nucleosomal DNA. Attar et al. demonstrate in vitro that purified frog ( Xenopus laevis ) histone H3-H4 tetramer presents a likely Cu2+ binding site using the specific configuration of Cys110 and His113 at the H3-H3 interface (see the figure). These results are consistent with previous observations that histones can bind divalent metal ions, proposed to store Zn2+ (zinc), detoxify Hg2+ (mercury), or regulate nucleosome architecture ([ 6 ][6], [ 7 ][7]). Additionally, this site binds heavy atoms that were used for the original phasing of the crystal structure ([ 8 ][8]). Multiple reductant molecules can be used by purified H3-H4 tetramers to convert Cu2+ to Cu+, including obligate two-electron donors. This observation raises interesting mechanistic questions worthy of further investigation, because one-electron reductions of Cu2+ to Cu+ are typically mediated by cofactors that can perform both one- and two-electron chemistry, such as flavins or quinones. ![Figure][9] Copper reductase Two histone H3 and two histone H4 molecules form a tetramer before being assembled into a nucelosome. Cys110 and His113 at the histone H3-H3 interface bind Cu2+, which is reduced to Cu+, involving the reductant cofactor nicotinamide adenine dinucleotide (NAD). GRAPHIC: C. BICKEL/ SCIENCE To test the relevance of this activity in cells, Attar et al. turned to the yeast S. cerevisiae . Although only His113 (and not Cys110) is conserved in S. cerevisiae (this seems to be a peculiarity of yeast), the H3-H4 tetramer also bound copper, albeit more weakly than in the purified tetramer from X. laevis . This offered the possibility not only to destroy the presumed activity by mutating His113 but also to “improve” it by reintroducing the missing Cys110, and to monitor the effects. Mutation of His113 of histone H3 in S. cerevisiae leads to slower growth and lower concentrations of intracellular Cu+, without affecting overall copper concentrations. Mutation of His113 affected the two most prominent roles for copper: Usage of oxygen for energy metabolism (respiration) and protection from oxygen-mediated damage by superoxide dismutase. Introduction of the missing Cys110 in the S. cerevisiae histone H3 increased intracellular amounts of Cu+ and resilience to limiting copper concentrations. Histones are rarely found in free form in the cell and, when not bound to DNA, are chaperoned by “storage proteins” ([ 9 ][10]). It is unknown if the copper reductase activity can be replicated in these contexts. The results obtained with live yeast cells suggest that this is the case, but technical limitations prevented the detection of copper reductase activity in the presence of DNA. Because copper reductase activity can only occur in the active site formed by the H3-H3 four helix bundle, a histone “chaperone” protein would have to bind an H3-H4 tetramer while still allowing enzymatic activity. Nevertheless, the findings of Attar et al. are potentially paradigm-shifting. Their discovery is of particular interest with respect to the evolution of histones and their adoption as packaging material for DNA. Histone-like proteins, often without the regulatory tails of eukaryotic histones, are found in many archaeal prokaryotes that typically have small genomes that do not require DNA compaction ([ 10 ][11], [ 11 ][12]). Perhaps the original role of histone proteins was to protect against oxygen toxicity, in response to the increase in oxygen concentrations that allowed for the evolution of eukaryotes and multicellular organisms. Further in vitro and in vivo characterization of the role of histones as copper reductases from archaeal organisms may provide valuable insight on this proposed role. 1. [↵][13]1. K. Luger et al ., Nature 389, 251 (1997). [OpenUrl][14][CrossRef][15][PubMed][16][Web of Science][17] 2. [↵][18]1. S. Henikoff , Curr. Biol. 27, R1118 (2017). [OpenUrl][19] 3. [↵][20]1. N. Attar et al ., Science 369, 59 (2020). [OpenUrl][21][Abstract/FREE Full Text][22] 4. [↵][23]1. K. A. Koch et al ., Chem. Biol. 4, 549 (1997). [OpenUrl][24][CrossRef][25][PubMed][26][Web of Science][27] 5. [↵][28]1. R. A. Saavedra , Science 234, 1589 (1986). [OpenUrl][29][FREE Full Text][30] 6. [↵][31]1. M. Adamczyk et al ., FEBS Lett. 581, 1409 (2007). [OpenUrl][32][CrossRef][33][PubMed][34][Web of Science][35] 7. [↵][36]1. W. Bal, 2. J. Lukszo et al ., Chem. Res. Toxicol. 8, 683 (1995). [OpenUrl][37][CrossRef][38][PubMed][39] 8. [↵][40]1. T. J. Richmond et al ., Nature 311, 532 (1984). [OpenUrl][41][CrossRef][42][PubMed][43][Web of Science][44] 9. [↵][45]1. Z. A. Gurard-Levin et al ., Annu. Rev. Biochem. 83, 487 (2014). [OpenUrl][46][CrossRef][47][PubMed][48] 10. [↵][49]1. F. Mattiroli et al ., Science 357, 609 (2017). [OpenUrl][50][Abstract/FREE Full Text][51] 11. [↵][52]1. P. B. Talbert et al ., Nat. Rev. Genet. 20, 283 (2019). 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Fitbit employees charged with possessing stolen Jawbone trade secrets

ZDNet

US prosecutors have charged six former and current Fitbit employees for knowingly possessing trade secrets stolen from Jawbone, Reuters reports. The six individuals all worked for the now-defunct Jawbone sometime between May 2011 and April 2015 before joining Fitibit. Jawbone sued Fitbit over stolen trade secrets in 2015, just ahead of Fitbit's IPO. The case was settled in December 2017, after Jawbone began shutting down operations. As Reuters notes, a federal administrative law judge found in a 2016 case -- involving the same individuals -- found "no Jawbone trade secrets were misappropriated or used in any Fitbit product, feature or technology."