Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

Interplay between DNA repair of the oxidatively modified base 8-oxo-7,8-dihydroguanine (OG) and transcriptional activation has been documented in mammalian genes. Previously, we synthesized OG into the VEGF potential G-quadruplex sequence (PQS) in the coding strand of a luciferase promoter to identify that base excision repair (BER) unmasked the G-quadruplex (G4) fold for gene activation. In the present work, OG was site-specifically synthesized into a luciferase reporter plasmid to follow the time-dependent expression in mammalian cells when OG in the VEGF PQS context was located in the coding vs template strands of the luciferase promoter. Removal of OG from the coding strand by OG glycosylase-1 (OGG1)-mediated BER upregulated transcription. When OG was in the template strand in the VEGF PQS context, transcription was downregulated by a BER-independent process. The time course changes in transcription show that repair in the template strand was more efficient than repair in the coding strand. Promoters were synthesized with an OG:A base pair that requires repair on both strands to yield a canonical G:C base pair. By monitoring the up/down luciferase expression, we followed the timing of repair of an OG:A base pair occurring on both strands in mammalian cells in which one lesion resides in a G-quadruplex loop and one in a potential i-motif. Depending on the strand in which OG resides, coding vs template, this modification is an up/downregulator of transcription that couples DNA repair with transcriptional regulation.

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“…These studies add support to a growing body of evidence and discussions that OG is an epigenetic-like modification to DNA. 3 , 4 , 10 − 15 …”

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confidence: 99%

8-Oxo-7,8-dihydroguanine in the Context of a Gene Promoter G-Quadruplex Is an On–Off Switch for Transcription

et al. 2017

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“…Moreover, interesting findings have recently shown how Pt-salts may increment ROS and DNA oxidation, leading to an increased cell death [64], and have suggested a possible use of APE1 redox inhibitors for the treatment/prevention of secondary effects like Pt-induced sensory neuropathy [88]. A further hypothesis regards the emerging discoveries about the non-canonical roles of BER proteins such as those associated with RNA metabolism [23], that could also explain the role of BER in Pt-salts induced effects. In fact, a strong but not completely characterized association between Pt-salts and RNA-damage, which inhibits ribosomal RNA synthesis in vivo [89] and mRNA translation in vitro [90], has been found.…”

Section: Discussionmentioning

confidence: 99%

“…Typically, BER is active in repairing non-bulky DNA lesions induced by oxidative, alkylating or methylation stressors [22]. Upon the recognition of the damaged base by specific glycosylases, the apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) cleaves the newly generated abasic site allowing the accomplishment of the DNA repair [23]. The pivotal role of APE1 is demonstrated by its function in cellular viability and embryonic development [24], due to its role in DNA repair activity and other recently characterized non-canonical functions.…”

Section: Introductionmentioning

confidence: 99%

“…The pivotal role of APE1 is demonstrated by its function in cellular viability and embryonic development [24], due to its role in DNA repair activity and other recently characterized non-canonical functions. In fact, APE1 also plays an important role as redox effector on many transcriptional factors, such as NF-κB, HIF-1α, STAT-3, PAX8, AP-1 and p53 [23][24][25][26][27], regulating important genes involved in tumor progression. Moreover, new interesting molecular functions involved in RNA metabolism were recently discovered in our laboratory [23], including processing of damaged RNA [28], miRNAs [29] and abasic and oxidized ribonucleotides embedded in DNA [30].…”

Section: Introductionmentioning

confidence: 99%

“…In fact, APE1 also plays an important role as redox effector on many transcriptional factors, such as NF-κB, HIF-1α, STAT-3, PAX8, AP-1 and p53 [23][24][25][26][27], regulating important genes involved in tumor progression. Moreover, new interesting molecular functions involved in RNA metabolism were recently discovered in our laboratory [23], including processing of damaged RNA [28], miRNAs [29] and abasic and oxidized ribonucleotides embedded in DNA [30]. The different functions of APE1 are finely modulated by expression, localization, posttranslational modifications (PTMs) [31][32][33][34][35][36] and by its protein-protein interactome, as well.…”

Section: Introductionmentioning

confidence: 99%

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APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

Malfatti

Gerratana

Dalla

et al. 2019

J Exp Clin Cancer Res

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Background Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors’ expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies. Methods We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels’ correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression. Results APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins. Conclusions APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches. Electronic supplementary material The online version of this article (10.1186/s13046-019-1294-9) contains supplementary material, which is available to authorized users.

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The roles of base excision repair enzyme OGG1 in gene expression

Wang

Hao

Pan

et al. 2018

Cell. Mol. Life Sci.

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Modifications of DNA strands and nucleobases—both induced and accidental—are associated with unfavorable consequences including loss or gain in genetic information and mutations. Therefore, DNA repair proteins have essential roles in keeping genome fidelity. Recently, mounting evidence supports that 8-oxoguanine (8-oxoG), one of the most abundant genomic base modifications generated by reactive oxygen and nitrogen species, along with its cognate repair protein 8-oxoguanine DNA glycosylase1 (OGG1), has distinct roles in gene expression through transcription modulation or signal transduction. Binding to 8-oxoG located in gene regulatory regions, OGG1 acts as a transcription modulator, which can control transcription factor homing, induce allosteric transition of G-quadruplex structure, or recruit chromatin remodelers. In addition, post-repair complex formed between OGG1 and its repair product-free 8-oxoG increases the levels of active small GTPases and induces downstream signaling cascades to trigger gene expressions. The present review discusses how cells exploit damaged guanine base(s) and the authentic repair protein to orchestrate a profile of various transcriptomes in redox-regulated biological processes.

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Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

Cited by 60 publications

References 131 publications

8-Oxo-7,8-dihydroguanine in the Context of a Gene Promoter G-Quadruplex Is an On–Off Switch for Transcription

8-Oxo-7,8-dihydroguanine in the Context of a Gene Promoter G-Quadruplex Is an On–Off Switch for Transcription

APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC

The roles of base excision repair enzyme OGG1 in gene expression

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