ROS and the DNA damage response in cancer

Srinivas, Upadhyayula Sai; Tan, Bryce W.Q.; Vellayappan, Balamurugan; Jeyasekharan, Anand D.

doi:10.1016/j.redox.2018.101084

Cited by 1,185 publications

(841 citation statements)

References 148 publications

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“…However, low rates of error during replication and DNA break-inducing mutagenic agents such as ionising radiation and reactive oxygen, while generating diversity for natural selection to act on (Tenaillon, Denamur, and Matic 2004), also adversely affect viability and could lead to diseases including cancer (Tomasetti, Li, and Vogelstein 2017;Srinivas et al 2019). Therefore, most cellular life forms invest in mechanisms that repair damaged DNA including double strand breaks (DSBs).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary and Comparative analysis of bacterial Non-Homologous End Joining Repair

Sharda

Badrinarayanan

Seshasayee

2019

Preprint

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DNA double-strand breaks (DSBs) are a threat to genome stability. In all domains of life, DSBs are faithfully fixed via homologous recombination. However, recombination requires the presence of an uncut copy of duplex DNA that can be used as a template for repair. Alternate to this, in the absence of a template, eukaryotes and some prokaryotes also utilize Non-homologous end joining (NHEJ) repair.This pathway, or variations of it, can be error-prone. However, it avoids the lethality of a DSB, making NHEJ an important form of repair. Although ubiquitously found in eukaryotes, NHEJ is not universally present in bacteria. It is unclear as to why many prokaryotic systems lack this pathway. To understand what could have led to the current distribution of NHEJ in bacteria, we carried out comparative genomics and phylogenetic analysis across ~6000 sequenced genomes. Our results show that this repair trait is sporadically distributed across the phylogeny, with a few clades that are completely devoid of it.Ancestral reconstruction suggests that NHEJ was absent in the eubacterial ancestor, followed by primary independent gains as well as secondary losses and gains, in different clades across the bacterial history. Further, our analysis suggests that this pattern of occurrence is consistent with the correlated evolution of NHEJ with key genome characteristics of genome size and growth rates; NHEJ presence in bacteria is associated with large genome sizes and / or slow growth rates, with the former being the dominant correlate. Given the central role these traits may play in determining the ability to carry out recombination, it is possible that the evolutionary history of bacterial NHEJ may have been shaped by the requirement for efficient DSB repair.

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Section: Introductionmentioning

confidence: 99%

Evolutionary and Comparative analysis of bacterial Non-Homologous End Joining Repair

Sharda

Badrinarayanan

Seshasayee

2019

Preprint

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“…Figure 2 displays that MET induces apoptosis and ROS generation; decreases mitochondrial membrane potential; up-regulates protein levels of Bax, Bak, Cyto-C, cleaved caspase-3, and cleaved caspase-9; and down-regulates Bcl-2 in the ACHN and A498 cells, thus indicating that MET exerts anticancer activity by increasing ROS production and inducing mitochondria-dependent apoptosis. In addition, as ROS have a short-half life, highly reactivity, and an electronegative oxygen, they can induce DNA damage and affect the DNA damage response [34]. Chemotherapeutic agents, such as doxorubicin and cisplatin, increase ROS levels, which contribute to their cytotoxicity by increasing DNA damage [35,36].…”

Section: Discussionmentioning

confidence: 99%

Metformin in combination with JS-K inhibits growth of renal cell carcinoma cells via reactive oxygen species activation and inducing DNA breaks

Zhao

Luo

et al. 2020

J. Cancer

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Metformin (MET) is taken as a principal medication for remedying Type 2 diabetes mellitus. Its anti-tumor effect has been reported increasingly, but the precise mechanism of it remains unclear. This study aims to explore the efficacy of MET and MET combined with nitric oxide donor prodrug JS-K on the proliferation, apoptosis, and DNA damage in human renal cell carcinoma (RCC) cells, and investigate the possible molecular mechanism involved. The cell proliferation was tested through methyl-tetrazolium assay and cell apoptosis was ascertained by flow cytometry. The dihydroethidium and JC-1 fluorescent methods were used to detect Reactive oxygen species (ROS) and mitochondrial transmembrane potential (Δψm), respectively. Proteins associated with apoptosis and DNA damage were evaluated by Western blotting. Results showed that MET and JS-K could suppress cell growth, and the inhibition concentration 50 of treatment with MET combined with JS-K (MET + JS-K) showed more toxicity than individual agents on RCC cells. This augmented toxicity was associated with intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential alteration, and induced DNA breaks. The results of Western blotting showed that the expression level of pro-apoptotic proteins, such as Bax, Bak, caspase-3, and caspase-9, was up-regulated, and the anti-apoptotic protein Bcl-2 was down-regulated after treatment using MET alone and MET + JS-K, correspondingly. Moreover, MET + JS-K inhibited the expression of cellular PCNA and Rad51, and immunofluorescence analysis of γH2AX proved that MET + JS-K enhanced DNA damage. In summary, the results of this research indicated that MET and JS-K inhibited RCC cell growth by activating ROS, targeting mitochondria-dependent apoptotic pathways, and inducing DNA breaks.

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“…Infection or chronic inflammation contributes to the occurrence of cancer mainly by leukocytes and immune cells in inflammatory lesions, which are activated by inflammation and produce ROS and reactive nitrogen species (RNS) [79,80]. ROS cause damage by oxidizing DNA (including point mutations, deletions, and gene reassortment), disrupting DNA repair, and posttranslationally modifying cancer proteins [81]. DNA damage is increased by the secretion of MIF from macrophages and T lymphocytes [82].…”

Section: Oxidative Stress and Tumorsmentioning

confidence: 99%

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

Xie

Lei

et al. 2020

BioMed Research International

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Inflammatory mediators and inflammatory cells in the inflammatory microenvironment promote the transformation of normal cells to cancer cells in the early stage of cancer, promote the growth and development of cancer cells, and induce tumor immune escape. The monomeric active ingredient β-elemene is extracted from the traditional Chinese medicine Curcuma wenyujin and has been proven to have good anti-inflammatory and antitumor activities in clinical applications for more than 20 years in China. Recent studies have found that this traditional Chinese medicine plays a vital role in macrophage infiltration and M2 polarization, as well as in regulating immune disorders, and it even regulates the transcription factors NF-κB and STAT3 to alter inflammation, tumorigenesis, and development. In addition, β-elemene regulates not only different inflammatory factors (such as TNF-α, IFN, TGF-β, and IL-6/10) but also oxidative stress in vivo and in vitro. The excellent anti-inflammatory and antitumor effects of β-elemene and its ability to alter the inflammatory microenvironment of tumors have been gradually elaborated. Although the study of monomeric active ingredients in traditional Chinese medicines is insufficient in terms of quality and quantity, the pharmacological effects of more active ingredients of traditional Chinese medicines will be revealed after β-elemene.

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ROS and the DNA damage response in cancer

Cited by 1,185 publications

References 148 publications

Evolutionary and Comparative analysis of bacterial Non-Homologous End Joining Repair

Evolutionary and Comparative analysis of bacterial Non-Homologous End Joining Repair

Metformin in combination with JS-K inhibits growth of renal cell carcinoma cells via reactive oxygen species activation and inducing DNA breaks

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

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