Reviews & Analysis

New work suggests that Prp8, a highly conserved protein in the heart of the spliceosome, both orients the substrate and participates in catalysis.

The tumor suppressor protein 53BP1 decorates DNA damage sites and is instrumental for nonhomologous end joining. Evidence that 53BP1 facilitates synapsis of DNA ends by modulating chromatin dynamics reveals a hitherto unanticipated strategy for joining distant ends.

A recent report shows that several 'poly-ADP-ribose-polymerases' may function exclusively as a family of endogenous mono-ADP-ribosyltransferases, providing a new, molecularly less complex and broadened cellular role for this elusive post-translational modification.

Analysis of in vivo and in vitro interactions between chaperonins and the whole spectrum of potential cytoplasmic substrates helps answer the vexed question of substrate specificity in the TRiC system.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. The N-end rule pathway, ubiquitin-dependent in eukaryotes, is also present in prokaryotes, which lack the ubiquitin system. An illuminating new study presents the crystal structure of a bacterial N-end rule recognition component in complex with a peptide containing a cognate degradation signal.

Much has been written and said about the links between the Ink4a-Arf locus, cellular senescence and stem-cell maintenance. Standing modestly in the shadows of these superstars of tumor suppression, the closely linked Ink4b gene is now emerging as a significant player in these events, and its regulation by a histone demethylase could provide new insights into how this remarkable locus is controlled.

In this issue of Nature Structural & Molecular Biology, work on the bacterial AAA+ machine ClpX provides insight into how the ATPase subunits exert a translocating force on their substrates.

The open gate of the BK-type K⁺ channel is stabilized when the voltage-sensor domains (VSDs) are activated by depolarization and the intracellular Mg²⁺ sensors are occupied. A systematic investigation reveals that each Mg²⁺ is bound by the transmembrane VSD and cytoplasmic ligand-sensing domain from two adjacent subunits, suggesting that relative positions of sensor and gate domains of BK channels may differ substantially from those suggested by homology models.

The Fanconi anemia pathway is part of the DNA-damage network including breast cancer–susceptibility proteins BRCA1 and BRCA2. This pathway is activated by the ataxia telangiectasia and Rad3–related (ATR) kinase, but the underlying mechanism remains unclear. A new study demonstrates that a major switch activating the pathway is the ATR-dependent phosphorylation of FANCI.

The Argonaute-1 (Ago1) protein bound to small interfering RNAs (siRNAs) directs heterochromatin formation in fission yeast. A high-throughput sequencing approach reveals that the composition of the Ago1-bound siRNA population is sensitive to the noncanonical poly(A) polymerase Cid14, indicating that the RNA-interference and Cid14-TRAMP RNA-degradation pathways compete for substrates in fission yeast.

By recruiting the Dnmt1 DNA methyltransferase to hemimethylated DNA, the ubiquitin-like with PHD and ring finger domains 1 (UHRF1) protein plays an important part in DNA methylation. The structures of the SRA domain of UHRF1 in complex with hemimethylated DNA show that the methylated cytosine is flipped out of the DNA helix, as observed previously with DNA methyltransferases.

Peroxisome proliferator–activated receptor-γ (PPARγ) is a ligand-regulated transcription factor with crucial roles in carbohydrate and lipid metabolism and adipogenesis, but the structural details of the binding and activation by endogenous ligands are not known. Two recent studies reveal how oxidized and nitrated fatty acids uniquely bind and activate PPARγ.

The crystal structure of the CSA-binding Duffy-binding-like domain DBL3x of the VAR2CSA-encoded PfEMP1 adhesin has been solved in the free state and complexed with CSA oligosaccharides, shedding light on the major host-parasite interaction in pregnancy-associated malaria.

Bacteria sequester key metabolic steps into polyhedral protein compartments. A newly discovered nanocompartment reveals what it takes for its cargo protein to become encapsulated within a protein shell.

Cohesin is a large ring-shaped protein complex that mediates cohesion between sister chromatids. New experiments show that the sister chromatids of a minichromosome are entrapped by monomeric cohesin rings, thus excluding the possibility that sister chromatid cohesion is mediated by nontopological interactions between cohesin complexes.

Transcriptional termination by RNA polymerase II in yeast occurs by two different pathways: stable or cryptic unstable transcripts use the Nrd1 complex, whereas mRNA uses 3′ cleavage and polyadenylation factors together with Rat1 exonuclease. How RNA polymerase II selects which pathway to use is discussed.

The exact mechanism by which cellular RNA polymerases translocate and maintain exceptionally high fidelity during transcription remains an important unresolved issue. Two recent structural studies of yeast RNA polymerase II in complex with its potent inhibitor, the fungal toxin α-amanitin, address this matter by describing crucial and surprising details about the dynamic organization of the enzyme catalytic center.