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In the Journal Club, Fabrizio d’Adda di Fagagna remembers how the work of Judy Campisi changed our understanding of cellular senescence and its effect on physiology and ageing, shaping the future of this research field.

Chromatin conformation and chromatin modifications affect DNA damage response signalling and hence the associated cellular outcomes of this response. This Opinion article discusses the implications of chromatin alterations in cancer cells on DNA damage responses.

D’Adda di Fagagna and colleagues observe that, after genotoxic treatment of cells and mice, unrepaired DNA-damage foci and DNA-damage signalling persist at telomeres. They show that introducing the telomeric protein TRF2 near a double-strand break elsewhere on the chromosomes prevents repair. Unrepaired foci are also observed at telomeres of ageing animals, suggesting a role for TRF2 in senescence establishment.

Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.

Cellular senescence is associated with ageing and cancerin vivoand has a proven tumour suppressive function. This Review discusses the evidence indicating that DNA damage and the engagement of the DNA-damage response pathways are common to both ageing and cancer.

Long non-coding RNAs transcribed at DNA damaged sites can play part in DNA damage response. Here the authors reveal that damaged induced lncRNAs can form DNA:RNA hybrids at resected DNA-ends. These hybrids are involved in recruiting HR-mediated repair machinery which, in turn, controls their level at DSBs.

Senescent cells alter their microenvironment by secreting a growing collection of factors, a phenomenon termed the senescence-associated secretory phenotype (SASP). Cellular senescence is often the result of nuclear DNA damage fuelling a chronic DNA damage response (DDR). Upstream elements of the DDR cascade are necessary for full blown SASP, and additional crosstalk occurs between the DDR and cytokine secretion.

Telomerase protects chromosome ends in stem cells and cancer cells. Here the authors show that Trimethylguaonsine Synthase 1 (TGS-1) – dependent trimethylguanosine capping of the RNA component of the human telomerase complex has an important role in directing telomere dependent telomere maintenance and suppressing the ALT pathway in cancer cells.

Various stress signals can induce a state of irreversible cell-cycle arrest that is known as cellular senescence. Understanding the causes of cellular senescence has provided insight into some of its consequences: it is important for suppressing cancer and possibly contributes to ageing.

Polycomb (PcG) proteins are known to promote cell proliferation by silencing expression of the tumour suppressor Ink4A-Arf. Piunti et al.show that PcG proteins also regulate tumour progression independently of this role, revealing a requirement for PRC1 and PRC2 in replication fork progression.

Tissue fluidification in invasive breast carcinoma is accompanied by mechanical stresses that compromise nuclear integrity and liberate DNA, resulting in the activation of a pro-inflammatory response that shape tumour evolution and progression.

An inspirational pioneer and leader in the field of cellular senescence.

Pessina et al. report that DNA damage induces the assembly of a functional promoter at double-strand breaks and the transcribed RNAs promote phase separation of damage-response factors such as 53BP1.

ALT cells use an alternative lengthening mechanism of telomeres and bear telomeric DNA damage with increased levels of damage-induced long non-coding RNA. Here the AUs show that antisense oligonucleotides (ASO) targeting such RNAs can induce ALT cancer cells selective cell death.

Assays in both C. elegans and human cells show that Notch interacts with ATM kinase to inhibit the DNA-damage response and that Notch activity is inversely correlated with ATM activation in breast cancer cells.

Loss of BRCA1 or BRCA2 results in genomic instability; however most studies have focused on the role of these proteins in double-strand break repair. Here the authors coupled cell line genetics and whole genome sequencing to investigate the formation of base substitutions and short indels in BRCA1-deficient cells, revealing a role for translesion DNA synthesis regulated by 53BP1.

Gioia, Tavella et al. show that severe acute respiratory syndrome coronavirus 2 causes DNA damage through CHK1 degradation and impairs 53BP1 recruitment to DNA lesions. The induced DNA damage is associated with expression of pro-inflammatory cytokines and senescence markers.

DNA double strand breaks (DSBs) are among the most deleterious types of damage and there is strong evidence indicating a relationship between breaks and transcription. Here the authors provide a high-resolution, genome-wide map of induced DSBs and observe ATM-dependent transcriptional repression.

Different mechanisms have been implicated in the induction of senescence. Two of these mechanisms, the DNA damage response, which induces a replicative checkpoint, and the formation of heterochromatic foci, which leads to transcriptional repression, are found to act together in oncogene-expressing cells.

The DNA damage response (DDR) involves site-specific small non-coding RNAs. Here the authors show that telomere dysfunction induces transcription of telomeric DNA damage response RNAs that are necessary for DDR activation, which can be specifically muted by antisense inhibitory oligonucleotides.

Michelini et al. show that RNA polymerase II is recruited to double-strand breaks to induce long non-coding RNAs and the generation of small DNA damage response RNAs that promote recruitment of DNA repair factors and repair.

This Review explores the intersection between cancer and aging, illustrating shared causal mechanisms including genome instability, telomere dysfunction, cellular senescence and dysregulated immunity and how these can be explored in animal models.

Cellular senescence is characterized by a permanent proliferation arrest and the establishment of a senescence-associated secretory phenotype. This Review discusses the mechanisms of cellular senescence and induction of a senescence-associated secretory phenotype, recent insights into how senescence contributes to ageing, and the potential of senolytic and senomorphic therapies in ageing and associated diseases.

Anna Uryga and Mandy Grootaert et al. combine cell culture and animal models to examine how senescence of human vascular smooth muscle cells (VSMCs) and persistent telomere damage drive inflammation. Their results suggest that telomere injury can be the primary cause of premature senescence in VSMCs, and that DNA damage can be a major cause of persistent inflammation in vascular disease.

Small non-coding RNAs have been implicated in the regulation of many processes; now a novel class of these RNAs is identified as having a role in the DNA-damage response.

Rossiello et al. review the contributions of telomere shortening and/or dysfunction to ageing and a broad spectrum of age-associated human diseases.

This protocol describes a method to sequence small RNAs by target enrichment (TEsR). By enriching for sRNAs, TEsR allows the quantitative detection of not only small RNAs but also their precursors and intermediate and mature forms.

RATaR (RNase A treatment and reconstitution) enables users to study the role of DNA damage response RNA (DDRNA) in the assembly of DNA damage response foci.