Volume 24 Issue 1, January 2017

Warfarin has been the most widely prescribed anticoagulant for decades. It functions by inhibiting the membrane enzyme vitamin K epoxide reductase (VKOR), but the molecular details of this effect have remained elusive. Two new studies shed light on the warfarin-VKOR interaction. The work has implications for precision medicine and could guide drug discovery.

Little is known about the functions of long noncoding RNAs compared with the amount of accumulated knowledge concerning protein-mediated mechanisms. A report now proposes a novel RNA classification based on similar kinetics of RNA synthesis, processing and turnover, and the authors predict that RNAs within each class might share functional properties.

The site of HIV genome integration is likely a contributing factor in viral gene expression, but such context-specific effects are difficult to demonstrate at the population level. A new approach overcomes this obstacle by tracking individual, barcoded viruses to investigate the relationship between integration site location and the corresponding viral transcription, thereby providing insights essential for understanding HIV production, latency and reactivation.

Determining the molecular mechanisms responsible for trinucleotide DNA repeat expansions is critical, as such expansions underlie many neuromuscular and neurodegenerative disorders. Mirkin and colleagues now propose that large-scale expansions of trinucleotide repeats can be generated by DNA-break-induced replication.

Loss of function of the CFTR anion channel leads to cystic fibrosis, the most common inherited condition in humans of European origin. A recently reported structure for CFTR at 3.7-Å resolution reveals an unexpected 'lasso' domain and provides new insights into channel function in healthy individuals and in people with cystic fibrosis.

Genetic and biochemical assays reveal that carbon monoxide produced by heme catabolism influences circadian rhythm in mammals by altering the activity of transcription factor CLOCK–BMAL1 at clock-gene targets.

The enzyme FICD was previously known to AMPylate the ER-resident chaperone BiP, inactivating the chaperone. Mammalian FICD is now shown to catalyze the removal of the AMP group from BiP.

New data reveal that telomere length is maintained in human pluripotent stem cells through the opposing activities of telomerase-meditated elongation and telomere trimming mechanisms promoted by HR factors.

Cryo-EM analysis captures three states of the human Rad51 recombinase and visualizes structures of presynaptic and postsynaptic filaments as well as a synaptic complex in the process of DNA-strand exchange.

Barcoded HIV ensembles (B-HIVE) provides a new approach to map HIV integration sites and to determine how genomic context influences proviral transcription activity and response to latency-reversing agents.

A newly developed assay in yeast reveals that large-scale expansions of trinucleotide repeats can occur in a single step, rather than through several small-scale events.

Large-scale sequencing approaches reveal that the genetic code of Euplotes ciliates supports widespread ribosomal frameshifting at stop codons, and that additional mechanisms are required for efficient translation termination.

Mass spectrometry and biochemical analyses reveal that the major form of VKOR found in cells features a disulfide bond between Cys51 and Cys132, and this intermediate is the target of the anticoagulant drug warfarin.

The binding sites for the anticoagulant drug warfarin and for vitamin K on the human VKOR are determined through biochemistry and computational approaches. The results indicate a competitive mechanism of inhibition of VKOR by warfarin.

Quantitative assessment of transcription, splicing, degradation, localization and translation of coding and noncoding genes allows classification of RNAs on the basis of their metabolism and may aid in inference of lncRNA function.