Volume 22 Issue 11, November 2015

Telomerase is a unique reverse transcriptase in that it repetitively uses a short piece of its RNA component as template to synthesize DNA. A new crystal structure of a part of the Tetrahymena telomerase ribonucleoprotein reveals how reverse transcription is limited to this specific template region.

Newly synthesized 60S ribosomal subunits are licensed for translation through the release of the antiassociation factor eIF6. A new study shows by cryo–electron microscopy how eIF6 eviction results from a long-range allosteric cascade that involves SBDS, the protein mutated in Shwachman-Diamond syndrome.

Deciphering the complexity of events at telomeres has enhanced understanding of how telomeres function to maintain genome integrity and how their dysfunction gives rise to human disease.

Telomerase is a nucleoprotein complex of a reverse transcriptase and an RNA that binds complementary telomeric-repeat DNA sequences and directs their extension. In this Commentary, the authors propose how hairpin structures formed by telomeric DNA repeats promote addition of telomerase repeats and why telomere sequences are evolutionarily conserved despite the problems that they pose to DNA replication.

Telomerase recruitment and activity are regulated by telomere-bound proteins that protect the chromosome ends. In this Perspective, the authors discuss recent advances in understanding how the interactions of shelterin and telomerase components contribute to telomere-length homeostasis.

Transcription of telomeres generates long noncoding RNAs (lncRNAs) composed of telomeric repeat sequences (TERRA) that hybridize with telomeric DNA and are components of telomeric heterochromatin. This Perspective considers the physiological roles of TERRA in telomere homeostasis and proposes that TERRA's functions are determined by the state of its telomere targets.

The shelterin complex sequesters the linear ends of chromosomes and prevents telomeres from being recognized as DNA double-strand breaks. In this Review, the authors discuss the complex interactions between shelterin components and DNA damage–response factors and consider shelterin's emerging roles as regulators of genome integrity and cell fate.

Genetic mutations that compromise telomere-length maintenance give rise to a group of related human diseases called telomere biology disorders. This Review discusses the molecular functions impaired by disease-associated mutations as well as modes of inheritance and clinical manifestations.

Cancer cells that lack telomerase activity can maintain telomere lengths that permit continued proliferation via a recombination-based pathway called alternative lengthening of telomeres (ALT). This Review summarizes recent insights into the mechanism of ALT function and how it is repressed in normal cells to permit telomere attrition that limits replication.

A crystal structure of the RNA-binding domain of Tetrahymena telomerase reverse transcriptase (TERT) with its template RNA (TER) reveals interactions that establish the template boundary element and direct the addition of telomeric DNA repeats.

ChIP-seq, biochemical and in vivo assays show that Rif1 binds G-rich motifs that can form G-quadruplex structures, thus regulating firing of proximal and distal DNA replication origins in fission yeast.

Solid-state and solution NMR spectroscopy provide insights into the chaperone αB-crystallin's highly dynamic assembly, which is instrumental in its distinct interactions with a wide range of structurally variable clients.

The E. coli GTPase HflX promotes ribosomal-subunit dissociation by inducing conformational changes in central intersubunit bridges and thereby rescues stalled ribosomes under heat-shock conditions.

During eukaryotic ribosome biogenesis, the nascent 60S subunit is activated by SBDS and GTPase EFL1. Cryo-EM and mutational analyses reveal how SBDS–EFL1 evicts antiassociation factor eIF6 from 60S and explain the effects of disease-related SBDS mutations.

A proteomics approach using MS2 as an RNA tag is used to provide snapshots of nascent preribosomal particles from budding yeast, thus allowing the determination of the stage-specific order in which 70 ribosome-assembly factors associate with pre-rRNA domains.

New crystal structures of the human endonuclease APE1 bound to substrate and product DNAs reveal the mechanism of recognition and processing of apurinic-apyrimidinic (AP) sites during base excision repair.

New analyses in S. pombe show that both the leading and lagging strands are replicated by DNA polymerase δ when stalled replication forks use homologous recombination to restart semiconservative DNA synthesis.

The progressive shortening of telomeres with each cell division determines cellular replicative capacity and ultimately induces cellular senescence. This Focus brings to light the complex interactions of telomerase and shelterin components in telomere length maintenance, the role of DNA damage-response factors in telomere replication and processing, and the consequences of telomere dysfunction in human disease and cancer cell proliferation.