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Some cancer cells lacking telomerase activity extend their telomeres via an alternative, recombination-based mechanism, termed ALT. A new study shows that depletion of histone chaperone ASF1 can induce ALT in both primary and cancer cells, suggesting that the ALT pathway may be triggered by changes in chromatin state.

Cells that bypass senescence in the absence of the p53 tumour suppressor protein have shortened telomeres that undergo fusion, and these fusions trigger mitotic arrest and cell death in crisis.

Dysfunctional telomeres activate innate immune responses through mitochondrial TERRA–ZBP1 complexes to eliminate cells that are destined for neoplastic transformation.

CYREN is a direct inhibitor of classical non-homologous end joining that promotes error-free repair by homologous recombination during the S and G2 phases of the cell cycle.

Here, the authors developed a method to precisely measure bulk, chromosome arm- and allele-specific human telomere length using nanopore sequencing. They resolve telomere shortening and differences between telomerase- and ALT-positive cancer cells

Mammalian telomeres are protected by shelterin components to avoid being recognized as DNA damage. Now cells under prolonged mitotic arrest are found to deprotect their telomeres, with dissociation of shelterin subunit TRF2 and degradation of the G-strand overhang. This leads to DNA damage signaling and checkpoint activation and apoptosis in the following G1 phase.

Mitotic catastrophe is a regulated mechanism that responds to aberrant mitoses leading to removal of damaged cells. Here the authors reveal how replication stress induces mitotic death through pathways regulated by WAPL and telomere deprotection.

Cell death during replicative crisis involves autophagy induced by telomere dysfunction.

An unstable genome is a hallmark of many cancer cells. Telomeres prevent the ends of linear chromosomes from being recognized as damaged DNA, thus protecting them from DNA repair mechanisms and inhibiting the breakage–fusion–bridge cycles that cause genome instability.

Telomere shortening, senescence and aging are connected, but how the signal at shortening telomeres is transmitted to the cell more globally is unclear. H3 and H4 synthesis is now shown to be reduced as cell cultures age. This alters expression of Asf1, a histone chaperone, compromising the ability of aging cells to restore chromatin after replication and DNA. In this way localized effects at shortening telomeres can be propagated throughout the cell.

Three recent studies reveal unexpected functions of Rap1, a member of the shelterin complex that protects chromosome ends from the activity of DNA repair pathways. Rap1 not only protects telomeres from sister chromatid exchange, but also functions in genome-wide transcriptional regulation and NF-κB-dependent signalling, revealing new perspectives for the telomere field.

Chromosome end protection is accomplished by telomeres. How cells cope with spontaneously unprotected telomeres while avoiding cell cycle arrest or cell death is a fascinating question.

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.

Two single-stranded DNA-binding proteins, POT1 and RPA, associate with telomeres. Binding of RPA to telomeres can activate a DNA damage response, so it was previously proposed that POT1 binds telomeres to prevent RPA association. Here, it is found that POT1–TPP1 cannot prevent RPA binding, and hnRNPA1 is identified as having this activity instead. In addition, it is shown that TERRA, a telomere-associated RNA, displaces hnRNPA1 and promotes POT1 binding after S phase, when replication is completed.

Protein complexes at telomeres have been assumed to present an obstacle to the passing replication fork. The observation that the Schizosaccharomyces pombe telomere-binding protein Taz1 is required for replication suggests otherwise.

Telomere dysfunction, usually owing to shortening, activates cellular senescence and can contribute to age-associated diseases and cancer. Mouse models are crucial for telomere research, but human and mouse telomeres have key differences. This Review discusses telomere maintenance and damage, and recent efforts to generate ‘humanized’-telomere mouse models.

Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells.

Telomeres, tandem repeats at the ends of linear chromosomes, have evolved to deal with the end replication and end protection. Using a proteomics approach, the authors identify TEBP-1 and TEBP-2, two double-stranded binding proteins which together are required for fertility. Despite being paralogs, they have distinct individual effects on telomere dynamics; TEBP-1 and TEBP-2 are part of a telomeric complex also containing POT-1.

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.

A hallmark of cancer cells is their ability to prevent telomere shortening. Sometimes this is achieved without telomerase by a process known as alternative lengthening of telomeres (ALT). Recent progress has been made in understanding how ALT occurs.

The multiprotein nuclear pore complexes (NPCs) that mediate nucleocytoplasmic transport are universal and essential for cell viability. However, cell type-specific expression of particular NPC components and specialized NPC functions now point towards a previously unrecognized heterogeneity in these ancient pores.