DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Wilhelm, Thérèse; Said, Maha; Naim, Valeria

doi:10.3390/genes11060642

Cited by 106 publications

(77 citation statements)

References 283 publications

(382 reference statements)

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“…Finally, regarding the timing of these events in ovarian cancer, it is known that FOXM1 is expressed in HGSC precursor lesions in the FTE, which may, along with other proteins such as cyclin E1, increase RS, thus providing a selective advantage for RHNO1 co-expression ( Karst et al, 2014 ; Levanon et al, 2014 ). Later during tumor progression, genomic instability functions as an important driver of continued RS independent of particular oncoproteins ( Passerini et al, 2016 ; Wilhelm et al, 2020 ). However, FOXM1 remains highly expressed because it promotes critical functions in late-stage progression unrelated to RS and genomic instability ( Halasi and Gartel, 2013a ; Kalathil et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

Barger

Chee

Albahrani

et al. 2021

eLife

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The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e., bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.

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Section: Discussionmentioning

confidence: 99%

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

Barger

Chee

Albahrani

et al. 2021

eLife

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“…Cr (III) forms DNA–protein crosslinks in human lung adenocarcinoma cells (A549) ( Macfie et al, 2010 ). SSBs and DSBs were found in rapidly dividing cells such as cancer cells as the collapse of replication fork during DNA replication, leading to cell cycle arrest and apoptosis via activation of p53 ( Lee et al, 2016 ; Wilhelm et al, 2020 ). In one study by Ueno et al SSBs were detected in the liver and kidney of male albino mice by a single injection of Cr (VI) but there were no significant levels of DNA strand breaks in the spleen, lung, or brain ( Urbano et al, 2012 ).…”

Section: Toxic Effects Of Heavy Metalsmentioning

confidence: 99%

Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and Arsenic

et al. 2021

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The industrial activities of the last century have caused massive increases in human exposure to heavy metals. Mercury, lead, chromium, cadmium, and arsenic have been the most common heavy metals that induced human poisonings. Here, we reviewed the mechanistic action of these heavy metals according to the available animal and human studies. Acute or chronic poisonings may occur following exposure through water, air, and food. Bioaccumulation of these heavy metals leads to a diversity of toxic effects on a variety of body tissues and organs. Heavy metals disrupt cellular events including growth, proliferation, differentiation, damage-repairing processes, and apoptosis. Comparison of the mechanisms of action reveals similar pathways for these metals to induce toxicity including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress. On the other hand, some of them have selective binding to specific macromolecules. The interaction of lead with aminolevulinic acid dehydratase and ferrochelatase is within this context. Reactions of other heavy metals with certain proteins were discussed as well. Some toxic metals including chromium, cadmium, and arsenic cause genomic instability. Defects in DNA repair following the induction of oxidative stress and DNA damage by the three metals have been considered as the cause of their carcinogenicity. Even with the current knowledge of hazards of heavy metals, the incidence of poisoning remains considerable and requires preventive and effective treatment. The application of chelation therapy for the management of metal poisoning could be another aspect of heavy metals to be reviewed in the future.

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“…A review in this special issue by Wilhelm et al described the major consequences of replicative stress during mitosis and its role in chromosomal instability (CIN) [199].…”

Section: Consequences During Mitosismentioning

confidence: 99%

A Link between Replicative Stress, Lamin Proteins, and Inflammation

Willaume

Rass

Fontanilla-Ramirez

et al. 2021

Genes

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Double-stranded breaks (DSB), the most toxic DNA lesions, are either a consequence of cellular metabolism, programmed as in during V(D)J recombination, or induced by anti-tumoral therapies or accidental genotoxic exposure. One origin of DSB sources is replicative stress, a major source of genome instability, especially when the integrity of the replication forks is not properly guaranteed. To complete stalled replication, restarting the fork requires complex molecular mechanisms, such as protection, remodeling, and processing. Recently, a link has been made between DNA damage accumulation and inflammation. Indeed, defects in DNA repair or in replication can lead to the release of DNA fragments in the cytosol. The recognition of this self-DNA by DNA sensors leads to the production of inflammatory factors. This beneficial response activating an innate immune response and destruction of cells bearing DNA damage may be considered as a novel part of DNA damage response. However, upon accumulation of DNA damage, a chronic inflammatory cellular microenvironment may lead to inflammatory pathologies, aging, and progression of tumor cells. Progress in understanding the molecular mechanisms of DNA damage repair, replication stress, and cytosolic DNA production would allow to propose new therapeutical strategies against cancer or inflammatory diseases associated with aging. In this review, we describe the mechanisms involved in DSB repair, the replicative stress management, and its consequences. We also focus on new emerging links between key components of the nuclear envelope, the lamins, and DNA repair, management of replicative stress, and inflammation.

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DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Cited by 106 publications

References 283 publications

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and Arsenic

A Link between Replicative Stress, Lamin Proteins, and Inflammation

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