Copper active sites in biology

[no abstract

Copper active sites in biology

[no abstract

Genomic footprints of activated telomere maintenance mechanisms in cancer

Abstract: Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer

Genomic footprints of activated telomere maintenance mechanisms in cancer

Abstract: Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer

Genomic footprints of activated telomere maintenance mechanisms in cancer

Abstract: Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer

Correlation of the Electronic and Geometric Structures in Mononuclear Copper(II) Superoxide Complexes

The geometry of mononuclear copper­(II) superoxide complexes has been shown to determine their ground state where side-on bonding leads to a singlet ground state and end-on complexes have triplet ground states. In an apparent contrast to this trend, the recently synthesized (HIPT₃tren)­Cu^IIO₂^•– (<b>1</b>) was proposed to have an end-on geometry and a singlet ground state. However, reexamination of <b>1</b> with resonance Raman, magnetic circular dichroism, and ²H NMR spectroscopies indicate that <b>1</b> is, in fact, an end-on superoxide species with a triplet ground state that results from the single Cu^IIO₂^•– bonding interaction being weaker than the spin-pairing energy

A N₃S_(thioether)-Ligated Cu^II-Superoxo with Enhanced Reactivity

Previous efforts to synthesize a cupric superoxide complex possessing a thioether donor have resulted in the formation of an end-on <i>trans</i>-peroxo-dicopper­(II) species, [{(Ligand)­Cu^II}₂(μ-1,2-O₂^2–)]²⁺. Redesign/modification of previous N₃S tetradentate ligands has now allowed for the stabilization of the monomeric, superoxide product possessing a S_(thioether) ligation, [(^DMAN₃S)­Cu^II(O₂^•–)]⁺ (<b>2</b>^<b>S</b>), as characterized by UV–vis and resonance Raman spectroscopies. This complex mimics the putative Cu^II(O₂^•–) active species of the copper monooxygenase PHM and exhibits enhanced reactivity toward both O–H and C–H substrates in comparison to close analogues [(L)­Cu^II(O₂^•–)]⁺, where L contains only nitrogen donor atoms. Also, comparisons of [(L)­Cu^II/I]ⁿ⁺ compound reduction potentials (L = various N₄ vs ^DMAN₃S ligands) provide evidence that ^DMAN₃S is a weaker donor to copper ion than is found for any N₄ ligand-complex

Peroxo and Superoxo Moieties Bound to Copper Ion: Electron-Transfer Equilibrium with a Small Reorganization Energy

Oxygenation of [Cu₂(UN-O^–)­(DMF)]²⁺ (<b>1</b>), a structurally characterized dicopper Robin–Day class I mixed-valent Cu­(II)­Cu­(I) complex, with UN-O^– as a binucleating ligand and where dimethylformamide (DMF) binds to the Cu­(II) ion, leads to a superoxo-dicopper­(II) species [Cu^II₂(UN-O^–)­(O₂^•–)]²⁺ (<b>2</b>). The formation kinetics provide that <i>k</i>_on = 9 × 10^–2 M^–1 s^–1 (−80 °C), Δ<i>H</i>^‡ = 31.1 kJ mol^–1 and Δ<i>S</i>^‡ = −99.4 J K^–1 mol^–1 (from −60 to −90 °C data). Complex <b>2</b> can be reversibly reduced to the peroxide species [Cu^II₂(UN-O^–)­(O₂^2–)]⁺ (<b>3</b>), using varying outer-sphere ferrocene or ferrocenium redox reagents. A Nernstian analysis could be performed by utilizing a monodiphenylamine substituted ferrocenium salt to oxidize <b>3</b>, leading to an equilibrium mixture with <i>K</i>_et = 5.3 (−80 °C); a standard reduction potential for the superoxo–peroxo pair is calculated to be <i>E</i>° = +130 mV vs SCE. A literature survey shows that this value falls into the range of biologically relevant redox reagents, e.g., cytochrome <i>c</i> and an organic solvent solubilized ascorbate anion. Using mixed-isotope resonance Raman (rRaman) spectroscopic characterization, accompanied by DFT calculations, it is shown that the superoxo complex consists of a mixture of μ-1,2- (<b>2</b>^<b>1,2</b>) and μ-1,1- (<b>2</b>^<b>1,1</b>) isomers, which are in rapid equilibrium. The electron transfer process involves only the μ-1,2-superoxo complex [Cu^II₂(UN-O^–)­(μ-1,2-O₂^•–)]²⁺ (<b>2</b>^<b>1,2</b>) and μ-1,2-peroxo structures [Cu^II₂(UN-O^–)­(O₂^2–)]⁺ (<b>3</b>) having a small bond reorganization energy of 0.4 eV (λ_in). A stopped-flow kinetic study results reveal an outer-sphere electron transfer process with a total reorganization energy (λ) of 1.1 eV between <b>2</b>^<b>1,2</b> and <b>3</b> calculated in the context of Marcus theory

Peroxo and Superoxo Moieties Bound to Copper Ion: Electron-Transfer Equilibrium with a Small Reorganization Energy

Oxygenation of [Cu₂(UN-O^–)­(DMF)]²⁺ (<b>1</b>), a structurally characterized dicopper Robin–Day class I mixed-valent Cu­(II)­Cu­(I) complex, with UN-O^– as a binucleating ligand and where dimethylformamide (DMF) binds to the Cu­(II) ion, leads to a superoxo-dicopper­(II) species [Cu^II₂(UN-O^–)­(O₂^•–)]²⁺ (<b>2</b>). The formation kinetics provide that <i>k</i>_on = 9 × 10^–2 M^–1 s^–1 (−80 °C), Δ<i>H</i>^‡ = 31.1 kJ mol^–1 and Δ<i>S</i>^‡ = −99.4 J K^–1 mol^–1 (from −60 to −90 °C data). Complex <b>2</b> can be reversibly reduced to the peroxide species [Cu^II₂(UN-O^–)­(O₂^2–)]⁺ (<b>3</b>), using varying outer-sphere ferrocene or ferrocenium redox reagents. A Nernstian analysis could be performed by utilizing a monodiphenylamine substituted ferrocenium salt to oxidize <b>3</b>, leading to an equilibrium mixture with <i>K</i>_et = 5.3 (−80 °C); a standard reduction potential for the superoxo–peroxo pair is calculated to be <i>E</i>° = +130 mV vs SCE. A literature survey shows that this value falls into the range of biologically relevant redox reagents, e.g., cytochrome <i>c</i> and an organic solvent solubilized ascorbate anion. Using mixed-isotope resonance Raman (rRaman) spectroscopic characterization, accompanied by DFT calculations, it is shown that the superoxo complex consists of a mixture of μ-1,2- (<b>2</b>^<b>1,2</b>) and μ-1,1- (<b>2</b>^<b>1,1</b>) isomers, which are in rapid equilibrium. The electron transfer process involves only the μ-1,2-superoxo complex [Cu^II₂(UN-O^–)­(μ-1,2-O₂^•–)]²⁺ (<b>2</b>^<b>1,2</b>) and μ-1,2-peroxo structures [Cu^II₂(UN-O^–)­(O₂^2–)]⁺ (<b>3</b>) having a small bond reorganization energy of 0.4 eV (λ_in). A stopped-flow kinetic study results reveal an outer-sphere electron transfer process with a total reorganization energy (λ) of 1.1 eV between <b>2</b>^<b>1,2</b> and <b>3</b> calculated in the context of Marcus theory