DNA Damage/Repair Management in Cancers

Alhmoud, Jehad F.; Woolley, J. C.; Moustafa, Ala-Eddin Al; Malki, Mohammed Imad

doi:10.3390/cancers12041050

Cited by 234 publications

(155 citation statements)

References 161 publications

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“…Double-strand breaks (DSBs) are the most deleterious type of DNA lesion and are induced in DNA by ionizing radiation, radiomimetic chemicals and cellular processes [1][2][3]. Theoretically, a single DSB may lead to cell death or initiate carcinogenesis if left unrepaired or repaired improperly [4].…”

Section: Global Versus Local Dsb Repair Pathway Selection and Regulationmentioning

confidence: 99%

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

Falk

Hausmann

2020

Cancers

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DNA double-strand breaks (DSBs) have been recognized as the most serious lesions in irradiated cells. While several biochemical pathways capable of repairing these lesions have been identified, the mechanisms by which cells select a specific pathway for activation at a given DSB site remain poorly understood. Our knowledge of DSB induction and repair has increased dramatically since the discovery of ionizing radiation-induced foci (IRIFs), initiating the possibility of spatiotemporally monitoring the assembly and disassembly of repair complexes in single cells. IRIF exploration revealed that all post-irradiation processes—DSB formation, repair and misrepair—are strongly dependent on the characteristics of DSB damage and the microarchitecture of the whole affected chromatin domain in addition to the cell status. The microscale features of IRIFs, such as their morphology, mobility, spatiotemporal distribution, and persistence kinetics, have been linked to repair mechanisms. However, the influence of various biochemical and structural factors and their specific combinations on IRIF architecture remains unknown, as does the hierarchy of these factors in the decision-making process for a particular repair mechanism at each individual DSB site. New insights into the relationship between the physical properties of the incident radiation, chromatin architecture, IRIF architecture, and DSB repair mechanisms and repair efficiency are expected from recent developments in optical superresolution microscopy (nanoscopy) techniques that have shifted our ability to analyze chromatin and IRIF architectures towards the nanoscale. In the present review, we discuss this relationship, attempt to correlate still rather isolated nanoscale studies with already better-understood aspects of DSB repair at the microscale, and consider whether newly emerging “correlated multiscale structuromics” can revolutionarily enhance our knowledge in this field.

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Section: Global Versus Local Dsb Repair Pathway Selection and Regulationmentioning

confidence: 99%

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

Falk

Hausmann

2020

Cancers

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“…Noticeably, base-excision repair was enriched in upregulated proteins. The base-excision repair pathway is a critical DNA repair system to correct damaged bases from oxidation, alkylation, and deamination [ 17 ]. Since DNA repair system is required to overcome platinum drug-induced DNA damages, up-regulation of base-excision repair pathway leads to oxaliplatin resistance [ 18 , 19 ].…”

Section: Resultsmentioning

confidence: 99%

SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells

Kim

Song

et al. 2021

Cancers

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Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed (thresholds of 2-fold changes and p-value ≤ 0.05) between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, cell cycle process, and type I interferon signaling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and Wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signaling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the oxaliplatin resistance.

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“…Defects in the DNA damage response (DDR) contributes to the genomic instability, and consequently aids in cancer initiation and progression [19]. Understanding the factors involved in DDR offers targetable vulnerabilities relatively speci c to cancer cells, which may bring potential bene t to clinical management [20].…”

Section: Discussionmentioning

confidence: 99%

TRAIP functions as an oncogene in hepatocellular carcinoma via Rb/EZH2/p21 signaling pathway

Luo¹,

Li²,

Zhang³

et al. 2020

Preprint

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Background The TRAF-interacting protein (TRAIP) has been identified as a master regulator of DNA damage and implicated in the progression of human cancers. Yet the underlying mechanism of TRAIP-mediated malignant phenotype remains unclear. Methods The expression of TRAIP in hepatocellular carcinoma (HCC) was examined by qRT-PCR, western blot and immunohistochemistry. The clinical significance of TRAIP was determined by Kaplan-Meier survival analyses. The biological function and the underlying mechanism of TRAIP in HCC progression were investigated, using cellular and molecular biological experiments.Results Here, we show that TRAIP is upregulated in HCC and functions as an oncogene via Rb/EZH2/p21 signaling. Overexpression of TRAIP, at both mRNA and protein levels, is correlated with more aggressive clinicopathological features, and unfavorable overall and disease-free survivals. In vitro experiments demonstrate that ectopic expression of TRAIP enhances, whereas knockdown of TRAIP attenuates HCC cell proliferation. Further data show that TRAIP interacts with SPAG5 in HCC cells, which results in the stabilization of TRAIP protein. TRAIP overexpression suppresses the expression of Rb, subsequently leading to the increase of EZH2 and decrease of p21. Re-expression of Rb and p21 significantly inhibits TRAIP-mediated cell growth. Conclusion Collectively, our findings suggest TRAIP exert oncogenic activity and have prognostic and therapeutic potential in HCC.

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DNA Damage/Repair Management in Cancers

Cited by 234 publications

References 161 publications

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells

TRAIP functions as an oncogene in hepatocellular carcinoma via Rb/EZH2/p21 signaling pathway

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