Deregulated expression of DNA polymerase β is involved in the progression of genomic instability

Luo, Qingying; Lai, Yanhao; Liu, Shukun; Wu, Mei; Liu, Yuan; Zhang, Zunzhen

doi:10.1002/em.21697

Cited by 13 publications

(19 citation statements)

References 27 publications

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“…Among the many reasons for TLS deregulation are changes in the expression of the polymerase catalyzing lesion bypass; mutations in the TLS polymerase itself reducing its fidelity or improving its competitiveness; and modulation of the interactions of a TLS polymerase with its protein partners. An increase in genomic instability, a hallmark of cancer, has been linked to the (i) hindering of the normal replicase operation, (ii) imbalances in expression of DNA polymerases, (iii) lack of a relatively accurate TLS “polymerase of choice” responsible for bypassing a particular lesion in normal cells, or (iv) outcompeting the polymerase by another, less accurate enzyme [reviewed in (Beagan and McVey, 2016; Ghosal and Chen, 2013; Guo et al , 2013; Jansen et al , 2015; Knobel and Marti, 2011; Lange et al , 2011; Loeb and Monnat, 2008; Luo et al , 2012; Makridakis and Reichardt, 2012; Nicolay et al , 2012b; Parsons et al , 2013; Pillaire et al , 2014; Sharma et al , 2013; Shcherbakova and Fijalkowska, 2006; Sweasy et al , 2006; Yousefzadeh et al , 2014)].…”

Section: Discussionmentioning

confidence: 99%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

224

204

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Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. “Hassle-free” DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves, are lesions that distort the structure of DNA. Despite elaborate systems that cells utilize to cleanse their genomes of damaged DNA, repair is often incomplete. The persistence of DNA lesions obstructing the cellular replicases can have deleterious consequences. One of the mechanisms allowing cells to complete replication is “Translesion DNA Synthesis (TLS). TLS is intrinsically error-prone, but apparently, the potential downside of increased mutagenesis is a healthier outcome for the cell than incomplete replication. Although most of the currently identified eukaryotic DNA polymerases have been implicated in TLS, the best characterized are those belonging to the “Y-family” of DNA polymerases (pols η, ι, κ, and Rev1), which are thought to play major roles in the TLS of persisting DNA lesions in coordination with the B-family polymerase, pol ζ. In this review, we summarize the unique features of these DNA polymerases by mainly focusing on their biochemical and structural characteristics, as well as potential protein-protein interactions with other critical factors affecting TLS regulation.

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Section: Discussionmentioning

confidence: 99%

Translesion DNA polymerases in eukaryotes: what makes them tick?

Vaisman

Woodgate

2017

Critical Reviews in Biochemistry and Molecular Biology

224

204

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“…It has been found that high level of pol β expression can promote DNA translesion synthesis in bypassing an O 6 -methylguanine (O 6 mG) by preferentially inserting a thymine resulting in a guanine to adenine transition mutation during the repair of alkylated DNA base lesions (Singh, et al, 1996; Wood and Shivji, 1997). Our previous study also suggests that overexpression of pol β induces base loss and/or base substitutions during BER that further lead to increased gene mutation frequency in cells (Luo, et al, 2012). …”

Section: Discussionmentioning

confidence: 82%

“…Pol β protein and mRNA level in pol β oe cells is 2.11-fold and 2.20-fold of those of pol β cells (Luo, et al, 2012). Cells were cultured in 5% CO 2 at 37 °C in Dulbecco’s modified eagle’s medium (DMEM) (Gibco, USA) supplemented with 10% fetal bovine serum (Fumeng Inc., China), 100 U/mL penicillin and 100 μg/mL streptomycin (Gibco, USA).…”

Section: Methodsmentioning

confidence: 99%

Involvement of DNA polymerase beta overexpression in the malignant transformation induced by benzo[a]pyrene

Zhao¹,

Wu²,

Lai³

et al. 2013

Toxicology

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Objective To explore the relationship between DNA polymerase β (pol β) overexpression and benzo[a]pyrene (BaP) carcinogenesis. Methods Firstly, mouse embryonic fibroblasts that express wild-type level of DNA polymerase β (pol β cell) and high level of pol β (pol β oe cell) were treated by various concentrations of BaP to determine genetic instability induced by BaP under differential expression levels of pol β. Secondly, malignant transformation of pol β cells by low concentration of BaP (20 μM) was determined by soft agar colony formation assay and transformation focus assay. Thirdly, the mRNA and protein levels of BaP-transformed pol β cells (named pol β-T cells) was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot, and the genetic instability of these cells were examined by HPRT gene mutation assay and random amplified polymorphic DNA (RAPD) assay. Results Pol β cells were successfully transformed into malignant pol β-T cells by an exposure to low concentration of BaP for 6 months. Pol β-T cells exhibited increased levels of pol β gene expression, HPRT gene mutation frequency and polymorphisms of RAPD products that were comparable to those of pol β oe cells. Conclusion Pol β overexpression and its-associated genetic instability may play a key role in BaP carcinogenesis.

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“…The cell viability was determined by 3-(4,5-dimethy thiazol2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, according to the method described previously with some modifications (Luo et al, 2012). Briefly, HepG2 cells were seeded in 96-well plates at a density of 2 × 10 4 cells (200 μL) per well.…”

Section: Cell Viability Measured By Mtt Assaymentioning

confidence: 99%

The role of NF-κB in PARP-inhibitor-mediated sensitization and detoxification of arsenic trioxide in hepatocellular carcinoma cells

et al. 2015

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-The therapeutic efficacy of arsenic trioxide (ATO) for treatments of solid tumors is restricted by its drug resistance and chemotoxicity. In this study, we investigated ATO sensitization and detoxification effect of the Poly (ADP ribose) polymerase-1 (PARP-1) inhibitor 4-Amino-1,8-naphthalimide (4AN) in the hepatocellular carcinoma cell line HepG2. We firstly reported that ATO treatment induced the activation of Nuclear factor of κB (NF-κB) and its downstream anti-apoptosis and pro-inflammatory effectors in a PARP-1-dependent manner and thus conferred HepG2 cells with ATO resistance and toxicity. 4AN significantly suppressed the ATO-induced NF-κB activation, which promotes the apoptotic response and alleviates the inflammatory reaction induced by ATO, resulting in sensitization and detoxification against ATO. We also demonstrated that the ATO-induced activation of PARP-1 and NF-κB was closely associated with the oxidative DNA damage mediated by the generated reactive oxygen species (ROS). Furthermore, the attenuation of ATO-induced ROS and the resulting oxidative DNA damage by N-acetyl-L-cysteine (NAC), a potent antioxidant, significantly reduced the activation of PARP-1 and NF-κB in ATO-treated cells. Our study provides novel insights into the mechanism of the PARP-1-mediated NF-κB signaling pathway in ATO resistance and toxicity in anticancer treatments. This study also highlights the application potential of PARP-1 inhibitors in ATO-based anti-cancer treatments and in prevention of NF-κB-mediated therapeutic resistance and toxicity.

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Deregulated expression of DNA polymerase β is involved in the progression of genomic instability

Cited by 13 publications

References 27 publications

Translesion DNA polymerases in eukaryotes: what makes them tick?

Translesion DNA polymerases in eukaryotes: what makes them tick?

Involvement of DNA polymerase beta overexpression in the malignant transformation induced by benzo[a]pyrene

The role of NF-κB in PARP-inhibitor-mediated sensitization and detoxification of arsenic trioxide in hepatocellular carcinoma cells

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