Base excision repair and its implications to cancer therapy

Grundy, Gabrielle J.; Parsons, Jason L.

doi:10.1042/ebc20200013

Cited by 69 publications

(50 citation statements)

References 108 publications

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“…Upregulation or down regulation of the BER pathway can lead to resistance or sensitivity, respectively, to these agents. Several inhibitors of the BER pathway are also in development ( Grundy et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Sobanski

Rose

Suraweera

et al. 2021

Front. Cell Dev. Biol.

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DNA repair and metabolic pathways are vital to maintain cellular homeostasis in normal human cells. Both of these pathways, however, undergo extensive changes during tumorigenesis, including modifications that promote rapid growth, genetic heterogeneity, and survival. While these two areas of research have remained relatively distinct, there is growing evidence that the pathways are interdependent and intrinsically linked. Therapeutic interventions that target metabolism or DNA repair systems have entered clinical practice in recent years, highlighting the potential of targeting these pathways in cancer. Further exploration of the links between metabolic and DNA repair pathways may open new therapeutic avenues in the future. Here, we discuss the dependence of DNA repair processes upon cellular metabolism; including the production of nucleotides required for repair, the necessity of metabolic pathways for the chromatin remodeling required for DNA repair, and the ways in which metabolism itself can induce and prevent DNA damage. We will also discuss the roles of metabolic proteins in DNA repair and, conversely, how DNA repair proteins can impact upon cell metabolism. Finally, we will discuss how further research may open therapeutic avenues in the treatment of cancer.

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Section: Introductionmentioning

confidence: 99%

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Sobanski

Rose

Suraweera

et al. 2021

Front. Cell Dev. Biol.

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“…Measuring just DNA strand breaks with the conventional comet assay gives limited information on the total and type of DNA damage induced, as the direct effect of some damaging agents will be the generation of modified bases (e.g., oxidative DNA damage), but also sites of base loss (apurinic/apyrimidinic or AP sites) that are alkali labile and therefore appear as breaks under alkaline comet assay conditions (pH > 13). AP sites will also be generated as intermediates during base excision repair of DNA base damage [ 8 ]. Moreover, it is generally accepted that, by performing the comet assay using neutral pH conditions (pH = 8), only DNA double strand breaks (DSBs) are detected, and there is plentiful published evidence to support this.…”

Section: Introductionmentioning

confidence: 99%

The Enzyme-Modified Neutral Comet (EMNC) Assay for Complex DNA Damage Detection

Fabbrizi

Hughes

Parsons

2021

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The comet assay is a versatile, simple, and sensitive gel electrophoresis–based method that can be used to measure and accurately quantify DNA damage, particularly single and double DNA strand breaks, in single cells. While generally this is used to measure variation in DNA strand break levels and repair capacity within a population of cells, the technique has more recently been adapted and evolved into more complex analysis and detection of specific DNA lesions, such as oxidized purines and pyrimidines, achieved through the utilization of damage-specific DNA repair enzymes following cell lysis. Here, we detail a version of the enzyme-modified neutral comet (EMNC) assay for the specific detection of complex DNA damage (CDD), defined as two or more DNA damage lesions within 1–2 helical turns of the DNA. CDD induction is specifically relevant to ionizing radiation (IR), particularly of increasing linear energy transfer (LET), and is known to contribute to the cell-killing effects of IR due to the difficult nature of its repair. Consequently, the EMNC assay reveals important details regarding the extent and complexity of DNA damage induced by IR, but also has potential for the study of other genotoxic agents that may induce CDD.

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“…Another study showed that APE1 redox inhibitors in combination with cisplatin inhibit proliferation of bladder cancer cells more efficiently than cisplatin alone (Fishel et al, 2019). Currently, specific inhibitors against BER proteins such as Polβ, PNKP, FEN1, Ligase IIIα, and PARP1/PARG have been developed either to sensitize several cancers or to form synthetic lethal partnerships with common cancer mutations (reviewed in Grundy and Parsons, 2020).…”

Section: Aberrant Repair Of Interstrand Dna Cross-linksmentioning

confidence: 99%

Role of Base Excision Repair Pathway in the Processing of Complex DNA Damage Generated by Oxidative Stress and Anticancer Drugs

Baiken

Kanayeva

Taipakova

et al. 2021

Front. Cell Dev. Biol.

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Chemical alterations in DNA induced by genotoxic factors can have a complex nature such as bulky DNA adducts, interstrand DNA cross-links (ICLs), and clustered DNA lesions (including double-strand breaks, DSB). Complex DNA damage (CDD) has a complex character/structure as compared to singular lesions like randomly distributed abasic sites, deaminated, alkylated, and oxidized DNA bases. CDD is thought to be critical since they are more challenging to repair than singular lesions. Although CDD naturally constitutes a relatively minor fraction of the overall DNA damage induced by free radicals, DNA cross-linking agents, and ionizing radiation, if left unrepaired, these lesions cause a number of serious consequences, such as gross chromosomal rearrangements and genome instability. If not tightly controlled, the repair of ICLs and clustered bi-stranded oxidized bases via DNA excision repair will either inhibit initial steps of repair or produce persistent chromosomal breaks and consequently be lethal for the cells. Biochemical and genetic evidences indicate that the removal of CDD requires concurrent involvement of a number of distinct DNA repair pathways including poly(ADP-ribose) polymerase (PARP)-mediated DNA strand break repair, base excision repair (BER), nucleotide incision repair (NIR), global genome and transcription coupled nucleotide excision repair (GG-NER and TC-NER, respectively), mismatch repair (MMR), homologous recombination (HR), non-homologous end joining (NHEJ), and translesion DNA synthesis (TLS) pathways. In this review, we describe the role of DNA glycosylase-mediated BER pathway in the removal of complex DNA lesions.

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Base excision repair and its implications to cancer therapy

Cited by 69 publications

References 108 publications

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

The Enzyme-Modified Neutral Comet (EMNC) Assay for Complex DNA Damage Detection

Role of Base Excision Repair Pathway in the Processing of Complex DNA Damage Generated by Oxidative Stress and Anticancer Drugs

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