The cGAS Paradox: Contrasting Roles for cGAS-STING Pathway in Chromosomal Instability

Hong, Christy; Tijhuis, Andréa E.; Foijer, Floris

doi:10.3390/cells8101228

Cited by 41 publications

(37 citation statements)

References 78 publications

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“…The accumulation of cytoplasmic ssDNA and dsDNA is also a common feature of tumours and cancer cell lines [34,55,56]. It has been proposed that DNA damage and replication stress elicit the activation of inflammatory responses that contribute to tumourigenesis in some contexts and to senescence/aging in others [57,58].…”

Section: Replication Stress Induces the Production Of Pro-inflammatormentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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Section: Replication Stress Induces the Production Of Pro-inflammatormentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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“…The capacity of tumors with CIN to activate or suppress immune signaling and to drive metastasis is an emerging area in cancer biology and immunotherapy [249,250]. By analyzing the genomic data of several human tumors from The Cancer Genome Atlas, Davoli and collaborators showed that high levels of arm-and whole-chromosome somatic copy number alterations (SCNAs) were correlated with the reduced expression of markers of cytotoxic immune cell types and proinflammatory cytokines and a suppressed response to checkpoint blockade immunotherapy [251].…”

Section: Emerging Concepts: Chromosomal Instability/aneuploidy Toleramentioning

confidence: 99%

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Wilhelm

Said

Naim

2020

Genes

106

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Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication stress”, a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies.

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“…It has been proved that DNA damage can trigger innate immune responses through the accumulation of nuclear DNA in the cytoplasm [ 56 , 57 ]. Furthermore, a common feature of tumors and cancer cell lines is the accumulation of cytoplasmic ssDNA and double-stranded (dsDNA) DNA [ 57 , 58 ]. Many human tumors display chromosome instability (CIN) phenotype, a condition as a result of which chromosome missegregation happens at increased frequency, and often coincides with cytosolic DNA that activate the cGAS- sensor protein stimulator of IFN genes (STING) pathway, forming an essential node between cancer cells and the immune microenvironment.…”

Section: At the Intersection Of Dna Damage And Innate Immunitymentioning

confidence: 99%

DNA Damage Response and Immune Defense

Nastasi

Mannarino

D’Incalci

2020

IJMS

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DNA damage is the cause of numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. The DNA damage response (DDR), in turn, coordinates DNA damage checkpoint activation and promotes the removal of DNA lesions. In recent years, several studies have shown how the DDR and the immune system are tightly connected, revealing an important crosstalk between the two of them. This interesting interplay has opened up new perspectives in clinical studies for immunological diseases as well as for cancer treatment. In this review, we provide an overview, from cellular to molecular pathways, on how DDR and the immune system communicate and share the crucial commitment of maintaining the genomic fitness.

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The cGAS Paradox: Contrasting Roles for cGAS-STING Pathway in Chromosomal Instability

Cited by 41 publications

References 78 publications

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

DNA Damage Response and Immune Defense

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