Exploiting DNA Replication Stress for Cancer Treatment

Ubhi, Tajinder; Brown, Grant W.

doi:10.1158/0008-5472.can-18-3631

Cited by 179 publications

(158 citation statements)

References 114 publications

(108 reference statements)

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“…A synergic relationship between the inactivation of replicative stress response inhibitors and replicative stress factors has been shown in clinical trials [247,248]. The new findings on the interaction of replicative stress and the innate immune response provide exciting novelties that can impact the development of new therapeutic strategies for cancer.…”

Section: Implications For Immunotherapymentioning

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: Implications For Immunotherapymentioning

confidence: 99%

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

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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“…Indeed, multiple signs of oncogene-induced replication stress and consequent DDR pathway activation are frequently observed in precancerous lesions. Recent therapeutic approaches have focused on identifying synthetic lethal interactions between cancer-associated mutations and DNA replication vulnerabilities (Ubhi and Brown, 2019). It has been proposed that, under specific conditions of oncogenic activation, inhibition of DDR proteins induces extensive replication stress, irreversible DSBs, and subsequent cell death, leading to selective elimination of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

DNA replication stress: oncogenes in the spotlight

Primo

Teixeira

2020

Genet. Mol. Biol.

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Precise replication of genetic material is essential to maintain genome stability. DNA replication is a tightly regulated process that ensues faithful copies of DNA molecules to daughter cells during each cell cycle. Perturbation of DNA replication may compromise the transmission of genetic information, leading to DNA damage, mutations, and chromosomal rearrangements. DNA replication stress, also referred to as DNA replicative stress, is defined as the slowing or stalling of replication fork progression during DNA synthesis as a result of different insults. Oncogene activation, one hallmark of cancer, is able to disturb numerous cellular processes, including DNA replication. In fact, extensive work has indicated that oncogene-induced replication stress is an important source of genomic instability in human carcinogenesis. In this review, we focus on main oncogenes that induce DNA replication stress, such as RAS, MYC, Cyclin E, MDM2, and BCL-2 among others, and the molecular mechanisms by which these oncogenes interfere with normal DNA replication and promote genomic instability.

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“…Claspin plays a role in DNA replication stress ( Lee et al 2012 ). It is known that there is an interplay between host immune systems and replication stress ( Ubhi and Brown 2019 ). The immune system can detect and respond to replication stress, which is an important feedback loop necessary to remove defective cells ( Liu et al 2015 ).…”

Section: Figure 8 Diagram Describing the Process Of Constructing Dirmentioning

confidence: 99%

Dense time-course gene expression profiling of the Drosophila melanogaster innate immune response

Schlamp

Delbare

Early

et al. 2020

Preprint

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Immune responses need to be initiated rapidly, and maintained as needed, to prevent establishment and growth of infections. Still, immune genes differ in both initiation kinetics and shutdown dynamics. Here, we performed an RNA-seq time course on D. melanogaster with 20 time points post-LPS injection. A combination of methods, including spline fitting, cluster analysis, and Granger Causality inference, allowed detailed dissection of expression profiles and functional annotation of genes through guilt-by-association. We identified antimicrobial peptides as immediate-early response genes with a sustained up-regulation up to five days after stimulation, and genes in the IM family as having early and transient responses. We further observed a strong trade-off with metabolic genes, which strikingly recovered to pre-infection levels before the immune response was fully resolved. This high-dimensional dataset enables the comprehensive study of immune response dynamics through the parallel application of multiple temporal data analysis methods.

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Exploiting DNA Replication Stress for Cancer Treatment

Cited by 179 publications

References 114 publications

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

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

DNA replication stress: oncogenes in the spotlight

Dense time-course gene expression profiling of the Drosophila melanogaster innate immune response

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