News & Views in 2016

Although oxidative stress has long been considered to be a major factor contributing to telomere shortening, recent work has established that oxidative stress and DNA damage are linked to telomere lengthening. Now, Opresko and colleagues resolve this apparent discrepancy by showing that differential modulation of telomerase activity depends on the origin of a common oxidative guanine lesion.

A conserved long noncoding RNA expressed at the 5S rDNA ribosomal locus has acquired a novel function in alternative-splicing regulation in primates, owing to the insertion of a mobile Alu element. This discovery opens new perspectives regarding the roles of transposable elements in expanding the human transcriptome and may be applied as a biotechnology tool to drive gene-specific changes in alternative splicing.

Drosophila Skywalker regulates the GTPase Rab35, thereby controlling the turnover of synaptic-vesicle proteins. A new crystal structure of the TBC domain of Skywalker reveals an unexpected phosphoinositide-binding pocket, which is critical for synaptic function and is disrupted in DOORS syndrome–causing mutations in the human Skywalker homolog TBC1D24.

The degradation of mRNAs involves removal of the 5′ protective cap via a decapping-enzyme complex, in a largely irreversible process that commits the transcript for destruction. Understanding how the decapping reaction is catalyzed and regulated are major goals in the field. New data suggest how the chemistry of decapping is controlled and orchestrated within the cell.

Methicillin resistance in the clinically important bacterium Staphylococcus aureus (MRSA) has evolved in multiple S. aureus lineages through acquisition of chromosomally integrating mobile genetic elements named SCCmec. Now Rice and colleagues show that the conserved SCCmec cch gene encodes an active DNA helicase, thus suggesting that extrachromosomal replication is part of the enigmatic SCCmec horizontal-transfer mechanism.

A potent toxin present in the venom of a fish-hunting cone snail is a minimized insulin (Con-Ins G1) lacking key residues involved in the receptor binding of most insulins. New data show that Con-Ins G1 nevertheless binds potently to the human insulin receptor, owing to a rearrangement that compensates for the lack of a critical binding residue.

Cells deploy the Hsp100 family of ATP-dependent machines to work with cellular chaperones in dismantling dangerous protein aggregates. New studies reveal an unprecedented spiral structure that provides mechanistic insight into the protein disaggregase Hsp104.

Forceful unfolding by entropic pulling is the general mechanism by which Hsp70 and Hsp110 chaperones control the oligomeric states, structures and activities of cellular proteins.

Bacteria and phages are engaged in a molecular arms race, constantly coevolving to best each other. The crystal structure of the anti-CRISPR protein AcrF3 bound to Cas3, an essential component of CRISPR-based immunity, sheds light on how phages have found ways to suppress bacterial immunity.

Mutations in the BRCA1 and BRCA2 genes strongly predispose carriers to breast and ovarian cancers. Two new studies reveal that FANCD2, a key component of the Fanconi anemia pathway, is essential for the survival of cells with BRCA1 or BRCA2 mutations. These findings pave the way for new 'synthetic lethal' strategies to kill BRCA-mutated cancers.

Ribosome profiling provides a snapshot of the mRNA positions of all elongating ribosomes in the cell. A new powerful enhancement of the technique, translation complex profile sequencing (TCP–seq), extends this mapping to scanning ribosomal complexes. In addition to its usefulness as a tool for studying the regulation of translation initiation, TCP–seq provides specific and powerful signatures of bona fide translation.

Unrestrained 53BP1 activity causes fusions of dysfunctional telomeres and embryonic lethality associated with misrepair of DNA double-strand breaks in BRCA1-deficient mice. However, the physiological role of 53BP1 remains unclear, because it presumably did not evolve to carry out these pathological functions. A new report proposes that 53BP1 activity prevents hyper-resection and thereby promotes error-free DNA repair while suppressing alternative mutagenic pathways.

The pathogenesis of the nerve paralysis induced by botulinum neurotoxins begins with their specific and high-affinity binding to peripheral nerve terminals. The new crystal structure of the toxin bound to its glycosylated receptor, presented in this issue, represents a major step forward in the understanding of how botulinum neurotoxin type A1, the toxin used in human therapy and cosmetics, binds its protein receptor.

Contrary to conventional wisdom that molecular chaperones rely on hydrophobic interactions to bind a wide variety of client proteins in danger of misfolding, three recent studies reveal that the ATP-independent chaperone Spy exploits electrostatic interactions to bind its clients quickly, yet loosely enough to enable folding of the client while it is chaperone bound.

Hydrogen/deuterium exchange mass spectrometry reveals that the antiapoptotic protein MCL-1 is inhibited by a covalent modification far from its functional site. This finding opens new avenues for cancer therapy, but it also highlights that much remains to be learned about the fundamental basis of allosteric regulation.

The noncoding RNA LINP1 acts as a scaffold that links Ku and DNA-PKcs and enables efficient DNA double-strand-break repair through nonhomologous end joining (NHEJ), thereby enhancing the resistance of triple-negative breast cancer cells to radiation and chemotherapies.

The importance of subtle gene regulation and epigenetics in determining complex human traits is increasingly being recognized. However, bridging the gaps between environmental, epigenetic and genetic influences and unraveling causal relationships remain a big challenge. A study now reports an example of epigenetic changes influenced by genetic factors that are involved in the regulation of lactase gene expression.

The first high-resolution views of group II intron maturases illuminate the architectural and functional roles of these multidomain proteins in splicing and DNA invasion. The maturases show striking structural and functional homology to a central protein involved in spliceosomal pre–messenger RNA splicing, thus reinforcing the idea that group II introns and the spliceosome descended from a common ancestor.

The sirtuin family protein SIRT6 is a stress-responsive NAD-dependent histone deacetylase with key roles in glucose homeostasis, DNA repair and cellular lifespan. SIRT6 is now shown to mediate deacetylation of histone H3 Lys18 specifically at pericentric chromatin, thus maintaining transcriptional silencing of satellite repeats in a manner independent of HP1 and trimethylated H3 Lys9, thereby assuring correct segregation of chromosomes.