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This Week in PNAS: Jul 27, 2010

In PNAS this week, researchers at Stanford and Tufts investigate various DNA sequences that can interfere with transcription and genomic stability because of their unusual structural properties. Sequences containing stretches of G-rich homopurine homopyrimidine are implicated in regulation of immunogenesis, genomic translocations, and telomere function, the researchers write. "Based upon the effects of various sequence modifications, solution conditions, and ribonucleotide substitutions, we conclude that transcription blockage is due to formation of unusually stable RNA/DNA hybrids, which could be further exacerbated by triplex formation," the team says. "These structures are likely responsible for transcription-dependent replication blockage by G-rich sequences in vivo."

Also in PNAS this week, researchers in Russia uncover links between mitochondrial respiration and the p53 pathway. While a shutdown of mitochondrial respiration doesn't trigger p53 response, strong p53 response is induced after the mitochondrial cytochrome bc1 is inhibited, the researchers write. "The p53 response is triggered by the deficiency in pyrimidines that is developed due to a suppression of the functionally coupled mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH)," they add. "The results establish the deficiency in pyrimidine biosynthesis as the cause of p53 response in the cells with impaired mitochondrial respiration."

In PNAS this week, collaborating researchers in California and China elucidate the Bruton tyrosine kinase inhibitor PCI-32765's role in blocking B-cell activation. PCI-32765 is currently under clinical development in patients with B-cell non-Hodgkins lymphoma, the researchers write. The inhibitor blocks B-cell antigen receptor signaling — the signaling pathway that contributes to the initiation and maintenance of B-cell malignancies — in human peripheral B-cells, without affecting T cell receptor signaling, the team adds. "These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway," the researchers write.

And in the PNAS Early Edition this week, researchers in Baltimore and China study the effect of D-peptide inhibitors on the p53-MDM2 interaction. The researchers say they recently indentified a D-peptide inhibitor termed DPMI-α that competes with p53 for MDM2 binding, and a D-peptide inhibitor termed DPMI-γ that binds MDM2. " Despite being resistant to proteolysis, both DPMI-α and DPMI-γ failed to actively traverse the cell membrane and, when conjugated to a cationic cell-penetrating peptide, were indiscriminately cytotoxic independently of p53 status," the researchers write. "Our findings validate D-peptide antagonists of MDM2 as a class of p53 activators for targeted molecular therapy of malignant neoplasms harboring WT p53 and elevated levels of MDM2."