Mechanisms of Oncogene-Induced Replication Stress: Jigsaw Falling into Place

Kotsantis, Panagiotis; Petermann, Eva; Boulton, Simon J.

doi:10.1158/2159-8290.cd-17-1461

Cited by 320 publications

(301 citation statements)

References 236 publications

(248 reference statements)

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“…Since components of pre-RC (Cdc6, Cdt1 and Geminin), components of the DNA replication elongation machinery (TICRR and MTBP), G1/S cell cycle transcriptional regulators (E2F1 and E2F3) and exonucleases (Exo1) have all been previously linked to the induction of DNA replication stress, we focused our study on these factors (Hills & Diffley, 2014;Kotsantis et al, 2018). We speculated that these interacting partners accumulate in CCNF K/O cell lines and exacerbate DNA replication stress upon Chk1 inhibition.…”

Section: E2f1 Promotes Dna Replication Catastrophe In Ccnf K/o Cells mentioning

confidence: 99%

“…Chk1 exerts this function by controlling the ubiquitylation and subsequent degradation of Cdc25A phosphatase (Busino et al, 2003;Jin et al, 2003;Kotsantis et al, 2018). Active ATR elicits a checkpoint response by phosphorylating Chk1 and initiating the signalling cascade that culminates with CDK inactivation.…”

Section: Introductionmentioning

confidence: 99%

“…Active ATR elicits a checkpoint response by phosphorylating Chk1 and initiating the signalling cascade that culminates with CDK inactivation. Chk1 exerts this function by controlling the ubiquitylation and subsequent degradation of Cdc25A phosphatase (Busino et al, 2003;Jin et al, 2003;Kotsantis et al, 2018). Cdc25A removes the inhibitory phosphorylation on Tyr15 of CDKs, mediated by the tyrosine kinase Wee1 to prompt CDK activation.…”

Section: Introductionmentioning

confidence: 99%

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E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

et al. 2019

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Cyclins are central engines of cell cycle progression in conjunction with cyclin‐dependent kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but instead forms via its F‐box domain an SCF (Skp1‐Cul1‐F‐box)‐type E3 ubiquitin ligase module. Although various substrates of cyclin F have been identified, the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging them with more than 180 different kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. Replication catastrophe depends on accumulation of the transcription factor E2F1 in cyclin F‐depleted cells. We find that SCF‐cyclin F controls E2F1 ubiquitylation and degradation during the G2/M phase of the cell cycle and upon challenging cells with Chk1 inhibitors. Thus, Cyclin F restricts E2F1 activity during the cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.

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Section: E2f1 Promotes Dna Replication Catastrophe In Ccnf K/o Cells mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

et al. 2019

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“…Metabolism reprogramming is a cellular adaptation to metabolic stress induced by oncogene expression (e.g. MYC) and stimuli from the tumor microenvironment . Reprogramming occurs when the metabolic network cannot meet the energetic and material demands required for the large number of physiological activities conducted simultaneously in cancer cells .…”

Section: Metabolic Stressmentioning

confidence: 99%

“…MYC) and stimuli from the tumor microenvironment. 76 Reprogramming occurs when the metabolic network cannot meet the energetic and material demands required for the large number of physiological activities conducted simultaneously in cancer cells. [77][78][79] Conflicts arise when the metabolic network attempts to coordinate the priorities of all "apparently essential" metabolic pathways, giving rise to metabolic stress.…”

Section: Metabolic Stressmentioning

confidence: 99%

Therapeutic targeting of cellular stress responses in cancer

Chen

Xie

2018

Thoracic Cancer

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Similar to bacteria, yeast, and other organisms that have evolved pathways to respond to environmental stresses, cancer cells develop mechanisms that increase genetic diversity to facilitate adaptation to a variety of stressful conditions, including hypoxia, nutrient deprivation, exposure to DNA‐damaging agents, and immune responses. To survive, cancer cells trigger mechanisms that drive genomic instability and mutation, alter gene expression programs, and reprogram the metabolic pathways to evade growth inhibition signaling and immune surveillance. A deeper understanding of the molecular mechanisms that underlie the pathways used by cancer cells to overcome stresses will allow us to develop more efficacious strategies for cancer therapy. Herein, we overview several key stresses imposed on cancer cells, including oxidative, metabolic, mechanical, and genotoxic, and discuss the mechanisms that drive cancer cell responses. The therapeutic implications of these responses are also considered, as these factors pave the way for the targeting of stress adaption pathways in order to slow cancer progression and block resistance to therapy.

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Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

Ahmed

Dröge

2019

Molecular Oncology

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Rapidly dividing cells maintain chromatin supercoiling homeostasis via two specialized classes of enzymes, DNA topoisomerase type 1 and 2 (TOP1/2). Several important anticancer drugs perturb this homeostasis by targeting TOP1/2, thereby generating genotoxic DNA damage. Our recent studies indicated that the oncofetal chromatin structuring high‐mobility group AT‐hook 2 (HMGA2) protein plays an important role as a DNA replication fork chaperone in coping with DNA topological ramifications that occur during replication stress, both genomewide and at fragile sites such as subtelomeres. Intriguingly, a recent large‐scale clinical study identified HMGA2 expression as a sole predicting marker for relapse and poor clinical outcomes in 350 acute myeloid leukemia (AML) patients receiving combinatorial treatments that targeted TOP2 and replicative DNA synthesis. Here, we demonstrate that HMGA2 significantly enhanced the DNA supercoil relaxation activity of the drug target TOP2A and that this activator function is mechanistically linked to HMGA2's known ability to constrain DNA supercoils within highly compacted ternary complexes. Furthermore, we show that HMGA2 significantly reduced genotoxic DNA damage in each tested cancer cell model during treatment with the TOP2A poison etoposide or the catalytic TOP2A inhibitor merbarone. Taken together with the recent clinical data obtained with AML patients targeted with TOP2 poisons, our study suggests a novel mechanism of cancer chemoresistance toward combination therapies administering TOP2 poisons or inhibitors. We therefore strongly argue for the future implementation of trials of HMGA2 expression profiling to stratify patients before finalizing clinical treatment regimes.

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Mechanisms of Oncogene-Induced Replication Stress: Jigsaw Falling into Place

Cited by 320 publications

References 236 publications

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

Therapeutic targeting of cellular stress responses in cancer

Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

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