The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond

Mirzayans, Razmik

doi:10.3390/ijms24076852

Cited by 2 publications

(1 citation statement)

References 13 publications

(16 reference statements)

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“…Polyploidy giant cancer cells (PGCCs) have been confirmed to possess cancer stem cell (CSC)-like characteristics, and give rise to progeny cells through asymmetric division which express epithelial-mesenchymal transition (EMT)-related markers thereby promoting invasion and migration [ 12 – 14 ]. Studies have shown that PGCCs generation was induced by anti-cancer therapies where the latter convert proliferating tumor into dormant cells [ 15 ]. The presence of PGCCs in OC has been preferentially reported in poor prognosis cancers participating in tumor relapse and therapy resistance [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

El Baba,

Haidar Ahmad,

Monnien

et al. 2023

Oncogene

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Human cytomegalovirus (HCMV) infection has been implicated in epithelial ovarian cancer (OC). Polyploidy giant cancer cells (PGCCs) have been observed in high-grade serous ovarian carcinoma (HGSOC); they possess cancer stem cell-like characteristics and give rise to progeny cells expressing epithelial-mesenchymal transition (EMT) markers. EZH2 plays a potential oncogenic role, correlating with high proliferative index and tumor grade in OC. Herein, we present the experimental evidence for HCMV as a reprogramming vector that elicited human ovarian epithelial cells (OECs) transformation leading to the generation of “CMV-transformed Ovarian cells” (CTO). The infection with the two high-risk clinical strains, namely HCMV-DB and BL provoked a distinct cellular and molecular mechanisms in infected OECs. EZH2 upregulation and cellular proliferation were curtailed by using EZH2 inhibitors. The HGSOC biopsies were characterized by an elevated EZH2 expression, possessing a strong positive correlation between the aforementioned marker and HCMV. From HGSOC biopsies, we isolated three HCMV clinical strains that transformed OECs generating CTO cells which displayed proliferative potentials in addition to EZH2 upregulation and PGCCs generation; these features were reduced upon EZH2 inhibition. High-risk HCMV strains transformed OECs confirming an HCMV-induced epithelial ovarian cancer model and highlighting EZH2 tumorigenic properties. Our findings might be highly relevant in the pathophysiology of ovarian tumors thereby nominating new targeted therapeutics.

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Section: Introductionmentioning

confidence: 99%

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

El Baba,

Haidar Ahmad,

Monnien

et al. 2023

Oncogene

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O⁶-Alkylguanine-DNA Alkyltransferase Maintains Genomic Integrity During Peroxynitrite-Mediated DNA Damage by Forming DNA-Protein Crosslinks

Chakraborty,

Mukherjee,

Chakrabarty

et al. 2024

Preprint

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Inflammation is an early immune response against invading pathogens and damaged tissue. Although beneficial, uncontrolled inflammation leads to various diseases and may be fatal. Peroxynitrite (PN) is a major reactive nitrogen species (RNS) generated during inflammation. It produces various DNA lesions including labile 8-nitroguanine which spontaneously converts into abasic sites resulting in DNA strand breakage. Here, we report the discovery of a previously unrecognized function of the human repair proteinO6-alkylguanine-DNA alkyltransferase (hAGT or MGMT). We showed that hAGT through its active site nucleophilic Cys145 thiolate can spontaneously react with 8-nitroguanine in DNA to form a stable DNA-protein crosslink (DPC). Interestingly, the process of DPC formation provides protection from PN-mediated genome instability. The Cys145-mutant of hAGT failed to form DPC and provide protection against inflammation-associated, PN-mediated cytotoxicity. Gel shift, dot blot and UV-Vis assays showed formation of a covalent linkage between PN-damaged DNA and hAGT through its active site Cys145. Finally, expression of hAGT was found to be significantly increased by induced macrophages and PN. The data presented here clearly demonstrated hAGT as a dual function protein that along with DNA repair is capable of maintaining genomic integrity and providing protection from the toxicity caused by PN-mediated DNA damage. Although DPCs may seem detrimental, there are multiple systems in place in normal cells for their repair.

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The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond

Abstract: A major challenge in treating patients with solid tumors is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes [...]

Cited by 2 publications

References 13 publications

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

O⁶-Alkylguanine-DNA Alkyltransferase Maintains Genomic Integrity During Peroxynitrite-Mediated DNA Damage by Forming DNA-Protein Crosslinks

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The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond

Abstract: A major challenge in treating patients with solid tumors is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes [...]

Cited by 2 publications

References 13 publications

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells

O6-Alkylguanine-DNA Alkyltransferase Maintains Genomic Integrity During Peroxynitrite-Mediated DNA Damage by Forming DNA-Protein Crosslinks

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O⁶-Alkylguanine-DNA Alkyltransferase Maintains Genomic Integrity During Peroxynitrite-Mediated DNA Damage by Forming DNA-Protein Crosslinks