ALTercations at telomeres: stress, recombination and extrachromosomal affairs.

Approximately 15% of human cancers depend on the alternative lengthening of telomeres (ALT) pathway to maintain telomeres and proliferate. Telomeres that are elongated using ALT display unique features raising the exciting prospect of tailored cancer therapies. ALT-mediated telomere elongation shares several features with recombination-based DNA repair. Strikingly, cells that use the ALT pathway display abnormal levels of replication stress at telomeres and accumulate abundant extrachromosomal telomeric DNA. In this review, we examine recent findings that shed light on the ALT mechanisms and the strategies currently available to suppress this telomere elongation mechanism.

The response to stressors in adulthood depends on the interaction between prenatal exposure to glucocorticoids and environmental context.

Maternal stress during reproduction can influence how offspring respond to stress later in life. Greater lifetime exposure to glucocorticoid hormones released during stress is linked to greater risks of behavioral disorders, disease susceptibility, and mortality. The immense variation in individual's stress responses is explained, in part, by prenatal glucocorticoid exposure. To explore the long-term effects of embryonic glucocorticoid exposure, we injected Japanese quail (Coturnix japonica) eggs with corticosterone. We characterized the endocrine stress response in offspring and measured experienced aggression at three different ages. We found that prenatal glucocorticoid exposure affected (1) the speed at which the stress response was terminated suggesting dysregulated negative feedback, (2) baseline corticosterone levels in a manner dependent on current environmental conditions with higher levels of experienced aggression associated with higher levels of baseline corticosterone, (3) the magnitude of an acute stress response based on baseline concentrations. We finish by proposing a framework that can be used to test these findings in future work. Overall, our findings suggest that the potential adaptive nature of prenatal glucocorticoid exposure is likely dependent on environmental context and may also be tempered by the negative effects of longer exposure to glucocorticoids each time an animal faces a stressor.

Perturbation of base excision repair sensitizes breast cancer cells to APOBEC3 deaminase-mediated mutations.

Abundant APOBEC3 (A3) deaminase-mediated mutations can dominate the mutational landscape ('mutator phenotype') of some cancers, however, the basis of this sporadic vulnerability is unknown. We show here that elevated expression of the bifunctional DNA glycosylase, NEIL2, sensitizes breast cancer cells to A3B-mediated mutations and double-strand breaks (DSBs) by perturbing canonical base excision repair (BER). NEIL2 usurps the canonical lyase, APE1, at abasic sites in a purified BER system, rendering them poor substrates for polymerase ß. However, the nicked NEIL2 product can serve as an entry site for Exo1 in vitro to generate single-stranded DNA, which would be susceptible to both A3B and DSBs. As NEIL2 or Exo1 depletion mitigates the DNA damage caused by A3B expression, we suggest that aberrant NEIL2 expression can explain certain instances of A3B-mediated mutations.

The rate of telomere loss is related to maximum lifespan in birds.

Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing. While the epidemiology, cellular and molecular biology of telomeres are well studied, a newer field exploring telomere biology in the context of ecology and evolution is just emerging. With work to date focusing on how telomere shortening relates to individual mortality, less is known about how telomeres relate to ageing rates across species. Here, we investigated telomere length in cross-sectional samples from 19 bird species to determine how rates of telomere loss relate to interspecific variation in maximum lifespan. We found that bird species with longer lifespans lose fewer telomeric repeats each year compared with species with shorter lifespans. In addition, phylogenetic analysis revealed that the rate of telomere loss is evolutionarily conserved within bird families. This suggests that the physiological causes of telomere shortening, or the ability to maintain telomeres, are features that may be responsible for, or co-evolved with, different lifespans observed across species.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.