R-Loops as Cellular Regulators and Genomic Threats

Molecular Cell, Journal Year: 2019, Volume and Issue: 73(3), P. 398 - 411

Published: Feb. 1, 2019

Language: Английский

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Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids

Cancer Discovery, Journal Year: 2018, Volume and Issue: 8(11), P. 1404 - 1421

Published: Sept. 13, 2018

Abstract Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset HGSCs actually functional defects remains unknown. Here, we devise a platform for profiling in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with homologous recombination (HR) and replication fork protection. Regardless gene mutational status, defect HR the organoids correlated PARP inhibitor sensitivity. A protection carboplatin CHK1 ATR Our results indicate that combination analysis testing allows identification targetable damage Larger numbers must be analyzed determine whether these assays can reproducibly predict patient response clinic. Significance: Patient-derived tumor grow rapidly match tumors which they derived, both genetically functionally. These used therapeutic sensitivity provide rapid means assessing parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404–21. ©2018 AACR. This article is highlighted In Issue feature, p. 1333

Language: Английский

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

Cancer Discovery, Journal Year: 2018, Volume and Issue: 8(5), P. 537 - 555

Published: April 13, 2018

Abstract Oncogene activation disturbs cellular processes and accommodates a complex landscape of changes in the genome that contribute to genomic instability, which accelerates mutation rates promotes tumorigenesis. Part this turmoil involves deregulation physiologic DNA replication, widely described as replication stress. Oncogene-induced stress is an early driver instability attributed plethora factors, most notably aberrant origin firing, replication–transcription collisions, reactive oxygen species, defective nucleotide metabolism. Significance: Replication fundamental step tumorigenesis has been associated with many activated oncogenes. Deciphering mechanisms response may provide new avenues for targeted cancer treatment. In review, we discuss latest findings on examine various through oncogenes induce Cancer Discov; 8(5); 537–55. ©2018 AACR.

Language: Английский

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RPA and RAD51: fork reversal, fork protection, and genome stability

Nature Structural & Molecular Biology, Journal Year: 2018, Volume and Issue: 25(6), P. 446 - 453

Published: May 24, 2018

Language: Английский

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Targeting ATR in cancer

Nature reviews. Cancer, Journal Year: 2018, Volume and Issue: 18(9), P. 586 - 595

Published: June 13, 2018

Language: Английский

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Doxorubicin—An Agent with Multiple Mechanisms of Anticancer Activity

Cells, Journal Year: 2023, Volume and Issue: 12(4), P. 659 - 659

Published: Feb. 19, 2023

Doxorubicin (DOX) constitutes the major constituent of anti-cancer treatment regimens currently in clinical use. However, precise mechanisms DOX’s action are not fully understood. Emerging evidence points to pleiotropic anticancer activity DOX, including its contribution DNA damage, reactive oxygen species (ROS) production, apoptosis, senescence, autophagy, ferroptosis, and pyroptosis induction, as well immunomodulatory role. This review aims collect information on DOX influence anti-tumor immune response, providing a rationale behind importance modern cancer therapy.

Language: Английский

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The plasticity of DNA replication forks in response to clinically relevant genotoxic stress

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(10), P. 633 - 651

Published: July 1, 2020

Language: Английский

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Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: July 24, 2020

Abstract Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity sensitivity ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive ATRi when combined with PARPi (PARPi-ATRi). Sensitivity PARPi-ATRi in diverse platinum-resistant models, including BRCA1/2 reversion CCNE1 -amplified correlate synergistic increases replication fork stalling, double-strand breaks, apoptosis. Surprisingly, BRCA mutations an ability form RAD51 foci frequently not observed models acquired PARPi-resistance, suggesting the existence alternative mechanisms. regardless mechanisms resistance, complete durable therapeutic responses significantly increase survival clinically relevant patient-derived xenografts (PDXs) models. These findings indicate a highly promising strategy for OVCAs acquire platinum.

Language: Английский

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An intrinsic S/G ₂ checkpoint enforced by ATR

Science, Journal Year: 2018, Volume and Issue: 361(6404), P. 806 - 810

Published: Aug. 23, 2018

An additional cell cycle checkpoint Cell division is controlled by checkpoints that regulate the temporal order of phases, including G 1 /S, 2 /M, and metaphase/anaphase transitions. Yet there are no known control mechanisms for a fourth fundamental transition—the S/G transition. Saldivar et al. report switchlike mechanism regulates The kinase ATR senses ongoing DNA replication in S phase represses mitotic transcriptional network, ensuring completed before mitosis. Science , this issue p. 806

Language: Английский

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DNA damage kinase signaling: checkpoint and repair at 30 years

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(18)

Published: Aug. 8, 2019

Language: Английский

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