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| Open AccessOsteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis
Glucocorticoids (GCs) inhibit bone angiogenesis and affect bone development, but the underlying mechanisms remain unclear. Here, the authors show that GCs induce vascular cell senescence during bone development by inhibiting angiogenin secretion from osteoclasts, impairing angiogenesis via endothelial Plexin B2, resulting in unpaired bone growth.
- Xiaonan Liu
- , Yu Chai
- & Mei Wan
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Article
| Open AccessCalcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging
Contacts between mitochondria and endoplasmatic reticulum (ER), and the transfer of calcium between them, have an important role in the regulation of cellular phenotypes, including senescence. Here the authors show that ITPR2 deficient mice display improved aging, associated with a decreased number of contacts between the mitochondria and the ER.
- Dorian V. Ziegler
- , David Vindrieux
- & David Bernard
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Article
| Open AccessAnti-senescent drug screening by deep learning-based morphology senescence scoring
Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Here, the authors develop a morphology-based deep learning system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells to evaluate the effects of anti-senescent reagents.
- Dai Kusumoto
- , Tomohisa Seki
- & Shinsuke Yuasa
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Article
| Open AccessTranscription-dependent cohesin repositioning rewires chromatin loops in cellular senescence
Senescence is a state of stable proliferative arrest. Here, the authors perform Hi-C analysis on oncogenic RAS-induced senescence in human fibroblasts and characterize the changes in the 3D genome folding associated with the senescence-specific gene expression profile, which are mediated in part through cohesin redistribution on chromatin.
- Ioana Olan
- , Aled J. Parry
- & Masashi Narita
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Article
| Open AccessG3BP1 controls the senescence-associated secretome and its impact on cancer progression
The mechanisms that control the deleterious behaviour of senescent cells is unclear. Here, the authors show that G3BP1 is required for the induction of the senescence-associated secretory phenotype (SASP), without affecting senescence, and that SASP secretion is a primary mediator of senescence-associated tumour growth.
- Amr Omer
- , Monica Cruz Barrera
- & Imed-Eddine Gallouzi
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Article
| Open AccessH3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients
Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.
- Kolja Schleich
- , Julia Kase
- & Clemens A. Schmitt
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Article
| Open AccessPersistent telomere cohesion protects aged cells from premature senescence
Telomere function is regulated by the telomere repeat binding proteins TRF1 and TRF2. Here the authors show that decreased levels of TRF1 proteins at shortened telomeres in aged human cells results in persistent telomere cohesion, protecting from premature senescence.
- Kameron Azarm
- , Amit Bhardwaj
- & Susan Smith
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Article
| Open AccessAn essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development
Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.
- Sunita Shankar
- , Jean Ching-Yi Tien
- & Arul M. Chinnaiyan
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Article
| Open AccessMitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
Mitochondria are a hub that can direct cellular outcomes in response to stress. Here, the authors show that mitochondrial phosphatase PGAM5 has a role in mitochondrial turnover and regulation of cellular senescence by altering organellar dynamics via fission regulator Drp1.
- Bo Yu
- , Jing Ma
- & Shusheng Wang
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Article
| Open AccessA BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
Senescent cells can influence the tumour microenvironment by secreting immunomodulatory factors and are thus a therapeutic target. Here, the authors identify a compound that degrades BET leading to DNA damage and activation of autophagy and a reduction in tumour growth.
- Masahiro Wakita
- , Akiko Takahashi
- & Eiji Hara
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Article
| Open AccessTopoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence
Here, the authors show that the topoisomerase 1-DNA covalent cleavage complex plays a critical role in mediating cytoplasmic chromatin fragments recognition by cyclic GMP-AMP synthase during senescence. The proposed axis is crucial to promote the inflammatory senescence-associated secretory phenotype and to enable the response to immune checkpoint blockade.
- Bo Zhao
- , Pingyu Liu
- & Rugang Zhang
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Article
| Open AccessInvolvement of condensin in cellular senescence through gene regulation and compartmental reorganization
Cell senescence involves stable arrest of cell proliferation and changes in gene expression and 3D genome reorganization. Here, the authors show that human condensin II complex participates in reorganization of the chromatin compartments, primarily through switching from heterochromatic B to euchromatic A compartments.
- Osamu Iwasaki
- , Hideki Tanizawa
- & Ken-ichi Noma
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Article
| Open AccessCSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence
Senescence of metabolically active cells is a process linked to ageing. Here the authors reveal that CSB is required to block replicative senescence, and epigenetic control of CSB downregulation triggers proliferative arrest in a p21-dependent manner.
- Clément Crochemore
- , Cristina Fernández-Molina
- & Miria Ricchetti
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Article
| Open AccessSenescent cell turnover slows with age providing an explanation for the Gompertz law
One of the underlying causes of aging is the accumulation of senescent cells, but their turnover rates and dynamics during ageing are unknown. Here the authors measure and model senescent cell production and removal and explore implications for mortality.
- Omer Karin
- , Amit Agrawal
- & Uri Alon
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Article
| Open AccessIdentification and characterization of Cardiac Glycosides as senolytic compounds
Senolytic compounds have the ability to eliminate senescent cells from tissues and have been shown to be beneficial in various animal models of age-related diseases. Here the authors show that cardiac glycosides commonly used for heart diseases have senolytic properties in humanized mouse models of tumorigenesis and lung fibrosis.
- Francisco Triana-Martínez
- , Pilar Picallos-Rabina
- & Manuel Collado
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Article
| Open AccessConnective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence
In regenerative animals, how cells respond to injury signals inducing senescence is unclear. Here, the authors show that cells from highly regenerative mammals are resistant to ROS-induced cellular senescence, but non-regenerating species exhibit mitochondrial dysfunction/senescence in response to hydrogen peroxide exposure.
- Sandeep Saxena
- , Hemendra Vekaria
- & Ashley W. Seifert
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Article
| Open AccessTyphoid toxin exhausts the RPA response to DNA replication stress driving senescence and Salmonella infection
Salmonella Typhi produces the typhoid toxin, which damages host cell DNA. Here, Ibler et al. show that the toxin induces a non-canonical DNA damage response mediated by the RPA pathway that drives host cell senescence and facilitates infection.
- Angela E. M. Ibler
- , Mohamed ElGhazaly
- & Daniel Humphreys
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Article
| Open AccessStabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis
DGCR8 is a component of the canonical microprocessor complex for microRNA biogenesis. Here the authors implicate DGCR8 in heterochromatin maintenance and aging attenuation independent of its miRNA-processing activity through Lamin B1, KAP1 and HP1 interaction. DGCR8 overexpression can alleviate aging and senescence
- Liping Deng
- , Ruotong Ren
- & Guang-Hui Liu
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Article
| Open AccessThe transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging
Muscle regeneration depends on self-renewal of muscle stem cells but how this is regulated on aging is unclear. Here, the authors identify Slug as regulating p16Ink4a in quiescent muscle stem cells, and when Slug expression reduces in aged stem cells, p16Ink4a accumulates, causing regenerative defects.
- Pei Zhu
- , Chunping Zhang
- & Wen-Shu Wu
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Article
| Open AccessCordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Radiation damage causes DNA foci to form and senescence, causing ulcers. Here, the authors show that a naturally occurring adenosine analogue, cordycepin, prevents cell senescence via an increase in AMPK/NRF2, so blocking ulcers caused by radiation on skin/intestine/tongue damage in rodents.
- Ziwen Wang
- , Zelin Chen
- & Chunmeng Shi
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Article
| Open AccessSenescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition
Senescent cells increase with ageing and may cause inflammatory conditions, but how this accumulation is mediated is still unclear. Here the authors show that senescent cells express HLA-E to suppress NKG2A-mediated natural killer and CD8 T cell activation to avoid targeted elimination, while blocking NKG2A helps promote immunity against senescent cells.
- Branca I. Pereira
- , Oliver P. Devine
- & Arne N. Akbar
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| Open AccessImpaired immune surveillance accelerates accumulation of senescent cells and aging
Senescent cells accumulate with aging contributing to age-related disease and the role of the immune system in removing senescent cells is not completely understood. Here, the authors show that perforin deficient mice accumulate more senescent cells and have a shorter lifespan, and that this phenotype can be reversed with administration of a senolytic drug.
- Yossi Ovadya
- , Tomer Landsberger
- & Valery Krizhanovsky
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Article
| Open AccessNuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation
Nestin can be localised in the nucleus of cancer cells, but its nuclear role in tumorigenesis is unclear. Here, the authors show that nuclear Nestin prevents senescence in tumor cells by stabilising lamin A/C from proteasomal degradation to maintain nuclear integrity.
- Yanan Zhang
- , Jiancheng Wang
- & Andy Peng Xiang
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Article
| Open AccessThe tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation
T cells can alter their metabolism during activation and differentiation. Here the authors show that the tumor suppressor menin regulates CD8 T-cell fate via the modulation of central carbon metabolism.
- Junpei Suzuki
- , Takeshi Yamada
- & Masakatsu Yamashita
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Article
| Open AccessRegulation of miR-181a expression in T cell aging
MicroRNA miR-181a has been implicated in the regulation of T cell activation and development. Here the authors show that miR-181a is regulated by a transcription factor, YY1, with reduced YY1 expression linked to reduced miR-181a in old individuals, while silencing YY1 impairs T cell functions largely through influencing the expression of miR-181a targets.
- Zhongde Ye
- , Guangjin Li
- & Jörg J. Goronzy
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Article
| Open AccessFoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence
Evidence for mitotic decline in aged cells and for aneuploidy-driven progression into full senescence is limited. Here, the authors find that in aged cells, mitotic gene repression leads to increased chromosome mis-segregation and aneuploidy that triggers permanent cell cycle arrest and full senescence.
- Joana Catarina Macedo
- , Sara Vaz
- & Elsa Logarinho
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Article
| Open AccessTGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging
Cellular senescence is associated with epigenetic remodeling. Here, the authors report that TGF-β signaling promotes miR-29 mediated loss of H4K20me3 thus accelerating senescence.
- Guoliang Lyu
- , Yiting Guan
- & Wei Tao
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Article
| Open AccessNOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence
Notch can drive senescence in a cell contact dependent manner. Here the authors show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously via the JAG1-NOTCH-HMGA1 interplay during senescence.
- Aled J. Parry
- , Matthew Hoare
- & Masashi Narita
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Article
| Open AccessThe RNA-binding protein YBX1 regulates epidermal progenitors at a posttranscriptional level
The integrity of the stratified epithelia relies on controlled cell turnover but it is unclear how mRNA binding proteins regulates this. Here, the authors show that the RNA binding protein Y-box binding protein-1 translationally represses cytokines, so preventing senescence and maintaining epidermal homeostasis.
- Eunjeong Kwon
- , Kristina Todorova
- & Anna Mandinova
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Article
| Open AccessDownregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells
Activation of DNA damage response induces the acquisition of senescence-associated secretory phenotype (SASP) in senescent cells, but precise mechanisms remain unclear. Here, the authors show that the cytoplasmic accumulation of nuclear DNA activated cytoplasmic DNA sensors to provoke SASP.
- Akiko Takahashi
- , Tze Mun Loo
- & Eiji Hara
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Article
| Open AccessParacrine cellular senescence exacerbates biliary injury and impairs regeneration
Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies.
- Sofia Ferreira-Gonzalez
- , Wei-Yu Lu
- & Stuart J. Forbes
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Article
| Open AccessRegulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
Regulatory T (Treg) cells can induce senescence of tumour-associated effector T cells, but it is not clear how. Here the authors show that Treg cells outcompete effector T cells for glucose uptake, resulting in activation of the DNA damage response in effector T cells.
- Xia Liu
- , Wei Mo
- & Guangyong Peng
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Article
| Open AccessDesumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway
Osteochondroprogenitors are essential cells for skeletal development and homeostasis. Here the authors show that the desumoylase SENP6 suppresses p53 activity by desumoylating and stabilising TRIM28, and that SENP6 ablation leads to skeletal abnormalities, senescence in osteochondroprogenitors and chondrocytes, and premature ageing.
- Jianshuang Li
- , Di Lu
- & Tao Yang
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Article
| Open AccessProgrammed cell senescence in skeleton during late puberty
Mesenchymal stem cells are essential for bone development, but it is unclear if their activity is maintained after late puberty, when bone growth decelerates. The authors show that during late puberty in mice, these cells undergo senescence under the epigenetic control of Ezh2.
- Changjun Li
- , Yu Chai
- & Mei Wan
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Article
| Open AccessIdentification of HSP90 inhibitors as a novel class of senolytics
The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.
- Heike Fuhrmann-Stroissnigg
- , Yuan Yuan Ling
- & Paul D. Robbins
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Article
| Open AccessATRX is a regulator of therapy induced senescence in human cells
Therapy induced senescence (TIS) is a growth suppressive program activated by cytostatic agents in some cancer cells. Here the authors show that the chromatin remodeling enzyme ATRX is a regulator of TIS and drives cells into this state via multiple mechanisms.
- Marta Kovatcheva
- , Will Liao
- & Andrew Koff
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Article
| Open AccessCellular senescence drives age-dependent hepatic steatosis
Non-alcoholic fatty liver disease is more common among older individuals. Here, the authors show that senescent cells in the liver promote fat accumulation and steatosis in the liver, and that clearance of senescent cells reduces hepatic steatosis in old, obese or diabetic mice.
- Mikolaj Ogrodnik
- , Satomi Miwa
- & Diana Jurk
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Article
| Open AccessSmall extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2
Although senescent cell secretome can promote the growth of surrounding cancer cells, the role of extracellular vesicles in this process has not been well understood. Here the authors show that ROS increase the sorting of EphA2 into extracellular vesicles in senescent cells, which promotes proliferation of cancer cells.
- Masaki Takasugi
- , Ryo Okada
- & Eiji Hara
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Article
| Open AccessExosomes maintain cellular homeostasis by excreting harmful DNA from cells
The role of exosomes in intercellular communication is well established, however less in known about the biological roles of exosome secretion in exosome-secreting cells. Here the authors show that exosome secretion controls cellular homeostasis in exosome-secreting cells by removing harmful cytoplasmic DNA from cells.
- Akiko Takahashi
- , Ryo Okada
- & Eiji Hara
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Article
| Open AccessHistone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression
Senescence of mammalian cells is characterized by proliferative arrest and expression of an inflammatory phenotype. Here the authors show the H2A variant H2A.J, found only in mammals, accumulates following persistent DNA damage or natural aging.
- Kévin Contrepois
- , Clément Coudereau
- & Carl Mann
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Article
| Open AccessCellular senescence mediates fibrotic pulmonary disease
Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.
- Marissa J. Schafer
- , Thomas A. White
- & Nathan K. LeBrasseur
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Article
| Open AccessStromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.
- Megan K. Ruhland
- , Andrew J. Loza
- & Sheila A. Stewart
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Article
| Open AccessDirected elimination of senescent cells by inhibition of BCL-W and BCL-XL
The accumulation of senescent cells within tissues plays a role in numerous age-related pathologies. Yosef and Pilpel et al. demonstrate that the resistance of these cells to apoptosis is driven by upregulation of survival proteins, whose pharmacological inhibition triggers senescent cell elimination in mice.
- Reut Yosef
- , Noam Pilpel
- & Valery Krizhanovsky
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Article
| Open AccessSCFFbxo22-KDM4A targets methylated p53 for degradation and regulates senescence
Cellular senescence—the permanent cessation of cell proliferation—is a process that can be deregulated in cancer and other aging-related diseases. Here the authors demonstrate that the SCFFbxo22-KDM4A complex plays an essential role during senescence as an E3 ligase that targets methylated p53 for degradation.
- Yoshikazu Johmura
- , Jia Sun
- & Makoto Nakanishi
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Article
| Open AccessDefective DNA single-strand break repair is responsible for senescence and neoplastic escape of epithelial cells
It is recognized that cellular senescence is triggered by DNA damage as a protective mechanism against tumorigenesis. Here the authors show that DNA single-strand breaks of oxidative origin can induce a transient senescent state followed by the emergence of clonal transformed cells.
- Joe Nassour
- , Sébastien Martien
- & Corinne Abbadie
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Article
| Open AccessNumb is required to prevent p53-dependent senescence following skeletal muscle injury
Regeneration of skeletal muscle relies on the function of muscle satellite cells. Here, Le Roux et al. show that the endocytic adaptor protein Numb promotes skeletal muscle regeneration after injury by preventing a p53-dependent senescence of satellite cells and consequent inflammation and fibrosis.
- Isabelle Le Roux
- , Julie Konge
- & Shahragim Tajbakhsh
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Article
| Open AccessTwo routes to senescence revealed by real-time analysis of telomerase-negative single lineages
Erosion of telomeres eventually causes replicative senescence, but mechanisms underlying the variability and dynamics of the pathway are not known. Here, the authors examine senescence in single yeast cells with inactivated telomerase to reveal two mechanistically distinct routes to senescence.
- Zhou Xu
- , Emilie Fallet
- & Maria Teresa Teixeira
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Article
| Open AccessHaploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence
BRCA1 functions in all cell types to help preserve genomic stability but oncogenesis is restricted to only a few tissues. Here Sedic et al. demonstrate a novel BRCA1haploinsufficiency-induced senescence pathway in epithelial cells.
- Maja Sedic
- , Adam Skibinski
- & Charlotte Kuperwasser
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The lncRNA MIR31HG regulates p16INK4A expression to modulate senescence
Oncogene-induced senescence (OIS) is a barrier to tumour progression. Here the authors identify the long non-coding RNA MIR31HG as a regulator of cellular senescence using the oncogene-induced senescence triggered by B-RAF expression in immortalized fibroblasts.
- Marta Montes
- , Morten M. Nielsen
- & Anders H. Lund