DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

Rossiello, Francesca; Aguado, Julio; Sepe, Sara; Iannelli, Fabio; Nguyen, Quan; Pitchiaya, Sethuramasundaram; Carninci, Piero; Fagagna, Fabrizio d’Adda di

doi:10.1038/ncomms13980

Cited by 87 publications

(121 citation statements)

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“…Indeed, DROSHA knockdown strongly impairs NHEJ repair efficiency to an extent similar to the inactivation of KU80, a central player in this repair pathway. Consistent with this result, a recent report from our group demonstrated that DROSHA inactivation results in a decrease in telomeric fusions, a process that relies on NHEJ (Rossiello et al, 2017).…”

Section: Discussionsupporting

confidence: 77%

“…Importantly, dilncRNA generation provides the RNA precursor for DDRNA generation upon DROSHA and DICER processing and, concomitantly, a sequence specific recruiting element for mature DDRNA together with DDR protein factors to which they associate . Similarly, we have shown that DDRNAs with telomeric sequences activate DDR at unprotected telomeres, which resemble DSBs (Rossiello et al, 2017). Interestingly, DROSHA inactivation by siRNA prevents telomere fusions.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported a role for DROSHA in DDR signaling (Francia et al, 2012), (Francia et al, 2016), , (Rossiello et al, 2017), (Pignataro et al, 2017), however its contribution to NHEJ, the main DSB repair pathway in mammalian cells, has not been yet clarified.…”

Section: Drosha Is Recruited At Dsbs Throughout the Cell-cyclementioning

confidence: 99%

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DROSHA associates to DNA damage sites and is required for DNA repair

Cabrini

Roncador

Galbiati

et al. 2018

Preprint

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The DNA damage response (DDR) is the signaling cascade through which a cell recognizes DNA lesions, and promotes their resolution via the repair pathways of Non-Homologous End Joining (NHEJ), or Homologous Recombination (HR). We recently demonstrated that DROSHA boosts DDR signaling by processing damage-induced long non-coding RNAs into smaller DNA damage response RNAs (DDRNAs). However, the location at which DROSHA exerts its DDR functions, relative to sites of DNA damage, remains unknown.To investigate DROSHA's localization during DDR activation, we used the DiVA cellular system, which allows the controlled induction of several DNA double strand breaks (DSBs) in the human genome. Indeed, by genome wide chromatin immunoprecipitation followed by next generation sequencing, we demonstrate that DROSHA associates with DSBs. In support of this, DSB-recruitment of DROSHA is detectable at the single-cell level by Proximity Ligation Assay between DROSHA and known DDR markers, and by DNA damage in situ ligation followed by Proximity Ligation Assay (DI-PLA), which demonstrates proximity of DROSHA to DNA ends. DROSHA recruitment occurs at both genic and inter-genic DSBs, suggesting that its recruitment is independent from ongoing transcription preceding damage generation. DROSHA's recruitment to DNA lesions occurs throughout the cell cycle, and with a preference for NHEJ-prone DSBs. Consistently, inhibition of the HR pathway increases DROSHA recruitment, and DROSHA knock down strongly impairs NHEJ efficiency in a GFP-reporter cellular system for monitoring NHEJ DNA repair. Overall, these results demonstrate that DROSHA acts locally at sites of DNA damage to promote NHEJ DNA repair.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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DROSHA associates to DNA damage sites and is required for DNA repair

Cabrini

Roncador

Galbiati

et al. 2018

Preprint

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“…Measures of telomere length are hampered by noise and wide longitudinal variations that cannot be explained by health events and at this stage are not useful for measuring biological age (Arai et al, 2015;Jodczyk, Fergusson, Horwood, Pearson, & Kennedy, 2014;Tomaska & Nosek, 2009). New methods are being developed, some of which are focused on detecting the DNA damage response (a typical marker of critical telomere shortening) may yield better results (Choi, Kim, Kim, Kemp, & Sancar, 2015;Hewitt et al, 2012;Rossiello et al, 2017). Senescence has been studied successfully in T lymphocytes, skin, and intramuscular fat, and high-throughput methods will be available soon (Evangelou et al, 2016;Lozano-Torres et al, 2017).…”

Section: Connec Ting the B I Ology Of Ag Ing With Ag E-a Sso Ciatedmentioning

confidence: 99%

Measuring biological aging in humans: A quest

et al. 2019

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The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

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“…Telomeric small RNAs have also been detected in mouse embryonic stem cells (Cao et al, 2009). Telomere dysfunction can induce production of telomeric siRNAs with perfect homology to the vertebrate telomere repeat sequence (TTAGGC)n, which are created by dsRNAs that arise from sites of DNA damage and are processsed by Dicer into siRNAs that promote the DNA damage response (Rossiello et al, 2017). However, the origin of small RNAs with homology to telomeres that are present under standard growth conditions of wildtype metazoan cells is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Telomeric small RNAs in the genus Caenorhabditis

Frenk¹,

Lister-Shimauchi

Ahmed³

2019

Preprint

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Telomeric DNA is composed of simple tandem repeat sequences and has a G-rich strand that runs 5' to 3' towards the chromosome terminus. Small RNAs with homology to telomeres have been observed in several organisms and could originate from telomeres or from interstitial telomere sequences (ITSs), which are composites of degenerate and perfect telomere repeat sequences found on chromosome arms. We identified C. elegans small RNAs composed of the Caenorhabditis telomere sequence (TTAGGC) n with up to three mismatches, which might interact with telomeres. We rigorously defined ITSs for genomes of C. elegans and for two closely related nematodes, C. briggsae and C. remanei. We found that most telomeric small RNAs with mismatches originated from ITSs, which were depleted from mRNAs and but were enriched in introns whose genes often displayed hallmarks of genomic silencing. C. elegans small RNAs composed of perfect telomere repeats were very rare but were increased by several orders of magnitude in C. briggsae and C. remanei. Major small RNA species in C. elegans begin with a 5' guanine nucleotide, which was strongly depleted from perfect telomeric small RNAs of all three Caenorhabditis species. Perfect telomeric small RNAs corresponding to the G-rich strand of the telomere commonly began with 5' UAGGCU and 5'UUAGGC, whereas C-rich strand RNAs commonly begin with 5'CUAAGC. In contrast, telomeric small RNAs with mismatches had a mixture of all four 5' nucleotides. Together, our results imply that perfect telomeric small RNAs have a mechanism of biogenesis that is distinct from known classes of small RNAs and that a dramatic change in their regulation occurred during recent Caenorhabditis evolution.

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DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

Cited by 87 publications

References 45 publications

DROSHA associates to DNA damage sites and is required for DNA repair

DROSHA associates to DNA damage sites and is required for DNA repair

Measuring biological aging in humans: A quest

Telomeric small RNAs in the genus Caenorhabditis

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