Cytotoxic and mutagenic properties of minor-groove O2-alkylthymidine lesions in human cells [DNA and Chromosomes]

April 23rd, 2018 by Jun Wu, Pengcheng Wang, Lin Li, Changjun You, Yinsheng Wang

Endogenous metabolism, environmental exposure, and cancer chemotherapy can lead to alkylation of DNA. It has been well documented that, among the different DNA alkylation products, minor-groove O2-alkylthymidine (O2-alkyldT) lesions are inefficiently repaired. In the present study, we examined how seven O2-alkyldT lesions, with the alkyl group being a Me, Et, nPr, iPr, nBu, iBu or sBu, are recognized by the DNA replication machinery in human cells. We found that the replication bypass efficiencies of these lesions decrease with increasing length of the alkyl chain, and that these lesions induce substantial frequencies of T→A and T→G mutations. Replication experiments using isogenic cells deficient in specific translesion synthesis (TLS) DNA polymerases revealed that the absence of polymerase η or polymerase ζ, but not polymerase κ or polymerase ι, significantly decreased both the bypass efficiencies and the mutation frequencies for those O2-alkyldT lesions carrying a straight-chain alkyl group. Moreover, the mutagenic properties of the O2-alkyldT lesions were influenced by the length and topology of the alkyl chain and by TLS polymerases. Together, our results provide important new knowledge about the cytotoxic and mutagenic properties of O2-alkyldT lesions, and illustrated the roles of TLS polymerases in replicative bypass of these lesions in human cells.

Evolution of chalcone isomerase from a noncatalytic ancestor

April 23rd, 2018 by Miriam Kaltenbach

Evolution of chalcone isomerase from a noncatalytic ancestor

Evolution of chalcone isomerase from a noncatalytic ancestor, Published online: 23 April 2018; doi:10.1038/s41589-018-0042-3

Ancestral sequence inference, directed evolution, structural analysis, NMR, and molecular dynamics simulations illuminate how enantioselective activity arises during the evolutionary trajectory of chalcone isomerase from a noncatalytic ancestor.

Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET

April 23rd, 2018 by Daria M. Shcherbakova

Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET

Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET, Published online: 23 April 2018; doi:10.1038/s41589-018-0044-1

The monomeric near-infrared (NIR) fluorescent protein miRFP720 enables development of fully NIR Förster resonance energy transfer (FRET) biosensors compatible with CFP–YFP FRET biosensors and blue–green optogenetic tools without optical cross-talk.
  • Posted in Nat Chem Biol, Publications
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Generalized extracellular molecule sensor platform for programming cellular behavior

April 23rd, 2018 by Leo Scheller

Generalized extracellular molecule sensor platform for programming cellular behavior

Generalized extracellular molecule sensor platform for programming cellular behavior, Published online: 23 April 2018; doi:10.1038/s41589-018-0046-z

Engineered erythropoietin receptor scaffolds equipped with extracellular sensor domains and modular intracellular domains that couple to endogenous signaling pathways enable modular reprogramming of designer membrane-bound receptors.
  • Posted in Nat Chem Biol, Publications
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Evolution of cyclohexadienyl dehydratase from an ancestral solute-binding protein

April 23rd, 2018 by Ben E. Clifton

Evolution of cyclohexadienyl dehydratase from an ancestral solute-binding protein

Evolution of cyclohexadienyl dehydratase from an ancestral solute-binding protein, Published online: 23 April 2018; doi:10.1038/s41589-018-0043-2

Ancestral protein reconstruction, with structural and biochemical analysis, illustrates the evolution of a solute-binding protein to cyclohexadienyl dehydratase through incorporation of a catalytic residue and gradual reshaping of the binding site.
  • Posted in Nat Chem Biol, Publications
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Understanding the Pro/N-end rule pathway

April 16th, 2018 by David A. Dougan

Understanding the Pro/N-end rule pathway

Understanding the Pro/N-end rule pathway, Published online: 16 April 2018; doi:10.1038/s41589-018-0045-0

Regulated destruction of proteins underlies just about everything a cell does. A structural study of human Gid4, the N-recognin of the Pro/N-end rule pathway that targets proteins through their N-terminal proline, illuminates the recognition of substrates by this proteolytic system.

Designing macrocyclic disulfide-rich peptides for biotechnological applications

April 16th, 2018 by Conan K. Wang

Designing macrocyclic disulfide-rich peptides for biotechnological applications

Designing macrocyclic disulfide-rich peptides for biotechnological applications, Published online: 16 April 2018; doi:10.1038/s41589-018-0039-y

Through molecular grafting, cyclic disulfide-rich peptides can be used as scaffolds to improve the stability, rigidity, and cellular uptake of bioactive peptides, although a number of factors should be considered when designing such grafted peptides.
  • Posted in Nat Chem Biol, Publications
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Dynamic coupling between conformations and nucleotide states in DNA gyrase

April 16th, 2018 by Aakash Basu

Dynamic coupling between conformations and nucleotide states in DNA gyrase

Dynamic coupling between conformations and nucleotide states in DNA gyrase, Published online: 16 April 2018; doi:10.1038/s41589-018-0037-0

Single-molecule measurements of DNA gyrase activity reveal conformational dynamics coupling ATP consumption to DNA supercoiling.
  • Posted in Nat Chem Biol, Publications
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Structure in sequence

April 16th, 2018 by Yiyun Song

Structure in sequence

Structure in sequence, Published online: 16 April 2018; doi:10.1038/s41589-018-0050-3

Structure in sequence

The peptide <span class=”small-caps”>d</span>-list

April 16th, 2018 by Mirella Bucci

The peptide d-list

The peptide <span class="small-caps">d</span>-list, Published online: 16 April 2018; doi:10.1038/s41589-018-0049-9

The peptide d-list