Cytoplasmic chromatin fragments—from mechanisms to therapeutic potential

Miller, Karl; Dasgupta, Nirmalya; Liu, Tianhui; Adams, Peter D.; Vizioli, Maria Grazia

doi:10.7554/elife.63728

Cited by 29 publications

(22 citation statements)

References 64 publications

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“…At least part of these DNA fragments exists in the form of large cytoplasmic chromatin fragments (CCFs). CCFs are lamin A/C-negative and strongly cH2AX-positive, and are generated by a nucleus-to-cytoplasm blebbing of chromatin [38][39][40]. Normally, cytosolic DNA is degraded by DNases, such as DNase2 and TREX1, or by autophagy/lysosomal pathways [36,41].…”

Section: Intrinsic Mechanism: Cgas-sting-mediated Regulationmentioning

confidence: 99%

Cellular senescence and the tumour microenvironment

2022

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The senescence‐associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP‐mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour‐suppressive and tumour‐promoting effects, as observed in senescence surveillance effects (tumour‐suppressive) and suppression of anti‐tumour immunity in most senescent cancer‐associated fibroblasts and senescent T cells (tumour‐promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context‐dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.

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Section: Intrinsic Mechanism: Cgas-sting-mediated Regulationmentioning

confidence: 99%

Cellular senescence and the tumour microenvironment

2022

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“…Finally, several other molecules have been proposed as senostatics, such as JAK inhibitors, JNK inhibitors, HDAC inhibitors and small molecule MDM2 antagonists. These molecules modulate (part of) the SASP, enhance mitochondrial activity and reduce cytoplasmic chromatin fragments in senescent cells [230][231][232].…”

Section: Sasp Inhibition: Senostatic/senomorphic Drugsmentioning

confidence: 99%

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease

et al. 2022

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Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver. Recent findings show that chronic oxidative stress can induce senescence, and this might be a driving mechanism for NAFLD progression, aggravating the disturbance of lipid metabolism, organelle dysfunction, pro-inflammatory response and hepatocellular damage. In this context, the modulation of cellular senescence can be beneficial to ameliorate oxidative stress-related damage during NAFLD progression. This review focuses on the role of oxidative stress and senescence in the mechanisms leading to NAFLD and discusses the possibilities to modulate senescence as a therapeutic strategy in the treatment of NAFLD.

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“…Cellular senescence can be induced by a variety of stimuli, including DNA damage, oncogene activation, telomere shortening, and mitochondrial dysfunction [55][56][57]. Micronuclei and cytosolic chromatin fragments are common senescence-associated phenotypic traits and influence the senescent state [58][59][60]. During the course of our characterization of the senescence parameters described above, we noticed that iKO cells frequently contained micronuclei whereas Flox cells did not (Fig 1C which Drosophila and mouse cells exposed to ionizing radiation and subjected to RNAimediated Arp2/3 depletion were found to contain DNA damage and micronuclei [27].…”

Section: The Formation Of Micronuclei and Dna Damage Clusters Precedes Iko Cell Senescencementioning

confidence: 99%

“…In addition to the above nuclear changes that took place upon Arp2/3 ablation, it seemed likely that cytoplasmic changes arising from the presence of micronuclei in ArpC2 iKO cells would also be linked to the onset of senescence. We hypothesized that a cytosolic DNA detection and signaling pathway involving the cyclic GMP-AMP Synthase (cGAS) enzyme, which recognizes extra-nuclear chromatin and relays a signal to the downstream effector molecule STING [60,68,69], might also be activated in iKO cells. Tagged cGAS can be recruited to micronuclei, and through its detection of cytosolic DNA and activation of STING, promotes pro-senescence and pro-inflammatory gene expression [70][71][72] We next wanted to determine the localization of endogenous cGAS and STING in the .…”

Section: Cytoplasmic Cgas and Sting Are Recruited To Micronucleimentioning

confidence: 99%

Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence

Campellone

Haarer

Guo

2022

Preprint

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The Arp2/3 complex is a ubiquitous actin nucleator with well-characterized activities in cell organization and movement, but its roles in chromatin-associated and cell cycle-related processes are relatively understudied. We investigated how the Arp2/3 complex affects genomic integrity, mitosis, and cell proliferation using mouse fibroblasts containing an inducible knockout (iKO) of the ArpC2 subunit. We show that permanent Arp2/3 ablation results in DNA damage, the formation of cytosolic micronuclei, and cellular senescence. Upon Arp2/3 depletion, cells undergo an abrupt proliferation arrest that is accompanied by activation of the tumor suppressor p53, upregulation of its downstream cell cycle inhibitor Cdkn1a/p21, and recognition of micronuclei by the cytosolic DNA sensor cGAS. Micronuclei arise in ArpC2 iKO cells due to chromosome segregation defects during mitosis and premature mitotic exits. Such phenotypes are explained by the presence of damaged chromatin fragments that fail to attach to the mitotic spindle, abnormalities in actin assembly during metaphase, and asymmetric microtubule architecture during anaphase. These studies establish functional requirements for the mammalian Arp2/3 complex in genome stability and mitotic spindle organization. They further expand our understanding of the intracellular mechanisms that lead to senescence and suggest that cytoskeletal dysfunction is an underlying factor in biological aging.

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Cytoplasmic chromatin fragments—from mechanisms to therapeutic potential

Cited by 29 publications

References 64 publications

Cellular senescence and the tumour microenvironment

Cellular senescence and the tumour microenvironment

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease

Genomic instability caused by Arp2/3 complex inactivation results in micronucleus biogenesis and cellular senescence

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