Dnase2a Deficiency Uncovers Lysosomal Clearance of Damaged Nuclear DNA via Autophagy

Lan, Yuk Yuen; Londoño, Diana; Bouley, Richard; Rooney, Michael S.; Hacohen, Nir

doi:10.1016/j.celrep.2014.08.074

Cited by 198 publications

(165 citation statements)

References 68 publications

(86 reference statements)

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“…Further mechanistic evidence supporting a link between DNA damage and STING-activated IFN pathways was provided by a study demonstrating that DNA damage or defects in the DNA repair system stimulate type I IFN expression in a STING-dependent manner (69). It was also revealed that DNA damage or a failure to repair DNA leads to the accumulation of cellular DNA in the cytoplasm, thus raising the question as to whether the proposed nuclear DNA sensing is in fact the sensing of DNA leaking into the cytoplasm (69)(70)(71). This issue needs further attention and will help clarify the involvement of DNA repair proteins in DNA-driven innate immunity.…”

Section: Interactions Between the Cgas-cgamp-sting Pathway And Othermentioning

confidence: 99%

Activation and Regulation of DNA-Driven Immune Responses

Paludan

2015

Microbiol Mol Biol Rev

108

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SUMMARY The innate immune system provides early defense against infections and also plays a key role in monitoring alterations of homeostasis in the body. DNA is highly immunostimulatory, and recent advances in this field have led to the identification of the innate immune sensors responsible for the recognition of DNA as well as the downstream pathways that are activated. Moreover, information on how cells regulate DNA-driven immune responses to avoid excessive inflammation is now emerging. Finally, several reports have demonstrated how defects in DNA sensing, signaling, and regulation are associated with susceptibility to infections or inflammatory diseases in humans and model organisms. In this review, the current literature on DNA-stimulated innate immune activation is discussed, and important new questions facing this field are proposed.

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Section: Interactions Between the Cgas-cgamp-sting Pathway And Othermentioning

confidence: 99%

Activation and Regulation of DNA-Driven Immune Responses

Paludan

2015

Microbiol Mol Biol Rev

108

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“…Two recent studies showed that damaged gDNA fragments are constitutively exported to lysosomes for degradation (Ivanov et al, 2013;Lan et al, 2014). Lack of co-localization of cytosolic 8OHdG(+) DNA and damaged (γ.H2A.X) or fragmented (TUN EL) gDNA markers rules out its nuclear origin (Fig.…”

Section: Res Ultsmentioning

confidence: 99%

Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus

Athale¹,

Domic²,

Murat³

et al. 2016

J Cell Biol

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“…Interestingly, DNA damage by irradiation or chemicals such as etoposide or cytosine arabinoside (Ara-C), is linked to type I IFN signaling (24)(25)(26). These DNA damaging agents lead to accumulation of cytosolic DNA and activate the IRF3 pathway.…”

mentioning

confidence: 99%

cGAS is essential for cellular senescence

Yang

Wang

Ren

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

749

733

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Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.ellular senescence is a state of irreversible cell cycle arrest triggered by various types of cellular and environmental stress, such as telomere shortening, oncogene activation, and DNA damage (1, 2). Senescence appears to be an antiproliferation process that limits the growth of damaged cells and acts as a potent barrier to tumorigenesis (3, 4). Senescence is characterized by several unique features, including enlarged and flattened cell morphology (5), increased senescence-associated β-galactosidase (SA-β-Gal) activity (6, 7), and in some cell types, a widespread change in chromatin modification, known as senescence-associated heterochromatin foci (SAHF) (7). At the molecular level, the p53-p21 WAF1 and pRb-p16 INK4a tumor suppressor pathways have been reported to be key mechanisms that control the execution and maintenance of senescence (8,9). In addition to these cellular features, senescent cells also undergo massive changes in the expression of genes that are thought to affect the tissue microenvironment (5). Senescent cells secrete a variety of soluble factors including inflammatory cytokines, growth factors, and proteases; such senescence-associated secretory phenotype (SASP) is a hallmark of senescence (10-12).Components of SASP not only serve as a marker of senescence, but also participate in the senescence process (13). Interleukin 6 (IL6) and IL8, two key components of SASP, reinforce the senescence growth arrest in neighboring cells (14,15). Additionally, these cytokines and other secreted factors attract immune cells, leading to the elimination of senescent cells (16). Given these important functions, SASP is regulated at both transcriptional and epigenetic levels, such as by nuclear factor κB (NF...

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Dnase2a Deficiency Uncovers Lysosomal Clearance of Damaged Nuclear DNA via Autophagy

Cited by 198 publications

References 68 publications

Activation and Regulation of DNA-Driven Immune Responses

Activation and Regulation of DNA-Driven Immune Responses

Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus

cGAS is essential for cellular senescence

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