DNA double strand break responses and chromatin alterations within the aging cell

Klement, Karolin; Goodarzi, Aaron A.

doi:10.1016/j.yexcr.2014.09.003

Cited by 39 publications

(16 citation statements)

References 157 publications

(222 reference statements)

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“…These effects of IZNP-1 on tumor cells were consistent with other reported telomeric G-quadruplex ligands. It is known that the accumulation of cells in the S phase is usually due to the induction of a DNA damage and repair pathway, and such events might result in cancer cell apoptosis (10,45). Thus, we proposed that IZNP-1 , as a telomeric multimeric G-quadruplex ligand, might induce telomere DNA damage, thereby arresting the cell cycle in the S phase and causing cell apoptosis accordingly.…”

Section: Resultsmentioning

confidence: 99%

“…A wealth of data indicates that telomeric G-quadruplex ligands, such as RHSP4, BRACO-19 and telomestatin, might interfere with telomere replication and disturb telomere capping (10–16), generating a telomere dysfunction in which the telomere architecture is disrupted (T-loop degradation), and chromosome ends are no longer properly protected. Without protection, telomeric ends would be rapidly recognized as damaged DNA and such an event would activate the DSB-mediated DNA damage response pathway (6,10,45). Moreover, uncapped telomeres can suffer degradation, inappropriate recombination, and end to end fusions and that telomere dysfunction can have an effect similar to that of DNA damage in eliciting cell cycle arrest, apoptosis and senescence (10,12).…”

Section: Resultsmentioning

confidence: 99%

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Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole

Chen

Wang

et al. 2016

Nucleic Acids Research

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Multiple G-quadruplex units in the 3΄-terminal overhang of human telomeric DNA can associate and form multimeric structures. The specific targeting of such distinctive higher-order G-quadruplexes might be a promising strategy for developing selective anticancer agents with fewer side effects. However, thus far, only a few molecules were found to selectively bind to telomeric multimeric G-quadruplexes, and their effects on cancer cells were unknown. In this study, a new triaryl-substituted imidazole derivative called IZNP-1 was synthesized and found to specifically bind to and strongly stabilize telomeric multimeric G-quadruplexes through intercalating into the pocket between the two quadruplex units. The pocket size might affect the binding behavior of IZNP-1. Further cellular studies indicated that IZNP-1 could provoke cell cycle arrest, apoptosis and senescence in Siha cancer cells, mainly because of telomeric DNA damage and telomere dysfunction induced by the interactions of IZNP-1 with telomeric G-quadruplexes. Notably, IZNP-1 had no effect on the transcriptional levels of several common oncogenes that have the potential to form monomeric G-quadruplex structures in their promoter regions. Such behavior differed from that of traditional telomeric G-quadruplex ligands. Accordingly, this work provides new insights for the development of selective anticancer drugs targeting telomeric multimeric G-quadruplexes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole

Chen

Wang

et al. 2016

Nucleic Acids Research

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“…Substrates of β-galactosidase include lactose, ganglioside GM1, lactosylceramides, and various glycoproteins [58]. Since β-galactosidase is highly expressed and accumulates in lysosomes in senescent cells, it is used as a senescence biomarker both in vivo and in vitro in qualitative and quantitative assays, despite its limitations [59, 60]. β-galactosidase expression and activity increases on platelet surfaces upon storage (K.M.H., unpublished data), presumably mediating surface terminal galactose cleavage, which may explain the exposure of βGlcNAc on platelet surface glycoconjugtes and clearance via macrophage αMβ2 integrin.…”

Section: Role Of Lysosomal Glycosidasesmentioning

confidence: 99%

Glycans and the platelet life cycle

Hoffmeister

Falet

2016

Platelets

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Platelet numbers are intricately regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. The growth factor thrombopoietin (TPO) drives platelet biogenesis by inducing megakaryocyte production. A recent study in mice identified a feedback mechanism by which clearance of aged, desialylated platelets stimulates TPO synthesis by hepatocytes. This new finding generated renewed interest in platelet clearance mechanisms. Here, different established and emerging mechanisms of platelet senescence and clearance will be reviewed with specific emphasis on the role of posttranslational modifications.

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“…41 In fact, stress-inducible senescence, which encompasses oncogene activation and exogenous stimuli (i.e., ionizing radiation), often occurs in a telomere-independent manner. The first strong evidence came from Serrano et al (1997) 42 in which RAS activation promoted permanent arrest in early G1 mediated by p53 and p16, a senescence-like phenotype.…”

Section: Senescence and Thyroid Cellsmentioning

confidence: 99%

Radiation-induced senescence and thyroid cancer: a barrier or a driving force

Penha

Lima

Pinto

2015

PAJAR, Pan Am. J. Aging Res.

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Aims: The main goal of this review-article was to shed light on the impact of senescence on thyroid carcinogenesis, a promising but still neglected field. Source of data: PubMed database and Google Scholar search was performed for English language articles with terms: ionizing radiation exposure, thyroid cancer, radiation signature, rET/PTC, senescence and radiation-induced senescence. We have no date restrictions. Summary of findings: Ionizing radiation (Ir) is undoubtedly the most well-characterized risk factor for thyroid cancer of the papillary histotype and its pivotal role as senescence inducer has been proposed. a paradoxical role of senescence on carcinogenesis -a barrier to cancer cell proliferation in early steps and a driving force to cancer progression by secreting proinflamatory cytokines and matrix degrading enzymes -is the heart of the matter of age-related cancer and bring to life new insights to thyroid cancer research field. This review-article briefly points out the major findings that link ionizing radiation to thyroid carcinogenesis, highlighting the molecular alterations mediated by acute and chronic radiation exposure in thyroid cells. Conclusions: Evidences provided by our group and other few reports suggest that, like other oncogenic stimuli in different cell types, Ir induces a senescent phenotype in thyroid cells, what could represent an initial barrier to transformation. However, how senescence could contribute to tumor progression still remains elusive. The comprehension of these mechanisms could not only help elucidating thyroid cancer initiation and progression, but could also indicate new therapeutical targets.Keywords: Ionizing radiation; Thyroid cancer; Senescence; DNa damage; rET/PTC. RESUMOObjetivos: O principal objetivo deste artigo de revisão foi lançar luz sobre o impacto da senescência na carcinogênese da tiroide, um campo promissor, mas ainda negligenciado. Fonte dos dados: pesquisa nos bancos de dados PubMed e Google Scholar realizada para artigos em inglês com os termos: exposição à radiação ionizante, câncer de tireoide, radiação assinatura, rET/PTC, senescência e senescência induzida por radiação. Não houve restrições quanto a data. Resumo das constatações: radiação ionizante (Ir) é, sem dúvida, o fator de risco mais bem caracterizado para o câncer de tireoide de histotipo papilar e seu papel central como indutor de senescência tem sido proposto. Um papel paradoxal da senescência na carcinogênese -uma barreira a proliferação celular cancerígena em etapas precoces e uma força motriz para a progressão do câncer através de secreção de citocinas pró-inflamatórias e enzimas matriz degradantes -é o foco principal sobre o câncer relacionado à idade e trazem à vida novos insights para a investigação do câncer de tiroide. Este artigo de revisão mostra brevemente as principais conclusões que apontam a radiação ionizante à carcinogênese de tireoide, destacando as alterações moleculares mediadas pela exposição aguda e crônica à radiação em células da tireoide. Conclusões:...

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DNA double strand break responses and chromatin alterations within the aging cell

Cited by 39 publications

References 157 publications

Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole

Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole

Glycans and the platelet life cycle

Radiation-induced senescence and thyroid cancer: a barrier or a driving force

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