Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage

Slyšková, Jana; Sabatella, Mariangela; Ribeiro-Silva, Cristina; Stok, Colin; Theil, Arjan F.; Vermeulen, Wim; Lans, Hannes

doi:10.1093/nar/gky764

Cited by 85 publications

(71 citation statements)

References 85 publications

(92 reference statements)

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“…Toxic effects of cisplatin and doxorubicin have been widely reported for these cell lines with a large range of IC 50 values observed (Table 1). BER proteins, including XRCC1, are involved in the repair of the platinum-DNA adducts, strand breaks, and DNA-protein crosslinks induced by these agents, though other repair pathways are more dominant [46–49].…”

Section: Resultsmentioning

confidence: 99%

Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

Lee

Piett

Andrews

et al. 2019

Preprint

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21 22 23DNA repair defects have been increasingly focused on as therapeutic targets. In hormone 24 positive breast cancer, XRCC1-deficient tumors have been identified and proposed as 25 targets for combination therapies that damage DNA and inhibit DNA repair pathways. 26XRCC1 is a scaffold protein that functions in base excision repair (BER) by mediating 27 essential interactions between DNA glycosylases, AP endonuclease, poly(ADP-ribose) 28 polymerase 1, DNA polymerase β (POL β), and DNA ligases. Loss of XRCC1 confers 29 BER defects and hypersensitivity to DNA damaging agents. BER defects have not been 30 evaluated in triple negative breast cancer (TNBC), for which new therapeutic targets and 31 therapies are needed. To evaluate the potential of XRCC1 as an indicator of BER defects 32 in TNBC, we examined XRCC1 expression and localization in the TCGA database and in 33 TNBC cell lines. High XRCC1 expression was observed for TNBC tumors in the TCGA 34 database and expression of XRCC1 varied between TNBC cell lines. We also observed 35 changes in XRCC1 subcellular localization in TNBCs that alter the ability to repair base 36 lesions and single-strand breaks. Subcellular localization changes were also observed for 37 POL β that did not correlate with XRCC1 localization. Basal levels of DNA damage were 38 also measured in the TNBC cell lines, and damage levels correlated with observed 39 changes in XRCC1 expression, localization, and repair functions. The results confirmed 40 that XRCC1 expression changes may indicate DNA repair capacity changes but 41 emphasize that basal DNA damage levels along with expression and localization are 42 better indicators of DNA repair defects. Given the observed over-expression of XRCC1 in 43 TNBC preclinical models and the TCGA database, XRCC1 expression levels should be 44 considered when evaluating treatment responses of TNBC preclinical model cells. 45 3 Keywords: triple negative breast cancer, base excision repair, XRCC1, PARP1, DNA 46 repair, DNA damage, nuclear localization 47 48 Defects in DNA damage response and repair are driving factors in carcinogenesis 49and key determinants in the response to chemotherapy. Breast cancers may display 50 defects in DNA repair such as mutations in key DNA damage response and repair 51 proteins such as breast cancer-susceptibility (BRCA1/2) and tumor suppressor protein 52 p53 (TP53), and altered expression levels of DNA repair proteins thymine-DNA 53 glycosylase (TDG) and poly(ADP-ribose) polymerase 1 (PARP1) [1-3]. Therapeutic 54 outcomes may be improved by exploiting DNA repair defects present in cancer cells but 55 absent in normal cells, as in the use of PARP-inhibitors (PARPi) in cancers that have 56 BRCA1/2 deficiencies. However, characterization of DNA repair pathways often is lacking 57 in preclinical models and cell lines. Examining DNA repair defects in preclinical models 58 and patients is essential for evaluating the efficacy of therapeutic agents. 59 In breast cancer, DNA repair defects often extend beyond homologous 60 re...

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Section: Resultsmentioning

confidence: 99%

Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

Lee

Piett

Andrews

et al. 2019

Preprint

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“…[4][5][6] The DDR comprises multiple pathways, each of which recognises and resolves specific types of DNA damage. Such damage includes large nucleotide adducts, which are resolved by nucleotide excision repair; small lesions, resolved by base excision repair; 7,8 and double-strand breaks (DSBs), resolved by pathways such as non-homologous end-joining (NHEJ) and homologous recombination (HR). 1,9,10 The various pathways involved in the DDR have been well studied at the molecular level, resulting in comprehensive mechanistic understanding behind their modes of action.…”

Section: Introductionmentioning

confidence: 99%

The roles of RNA in DNA double-strand break repair

et al. 2020

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Effective DNA repair is essential for cell survival: a failure to correctly repair damage leads to the accumulation of mutations and is the driving force for carcinogenesis. Multiple pathways have evolved to protect against both intrinsic and extrinsic genotoxic events, and recent developments have highlighted an unforeseen critical role for RNA in ensuring genome stability. It is currently unclear exactly how RNA molecules participate in the repair pathways, although many models have been proposed and it is possible that RNA acts in diverse ways to facilitate DNA repair. A number of well-documented DNA repair factors have been described to have RNA-binding capacities and, moreover, screens investigating DNA-damage repair mechanisms have identified RNA-binding proteins as a major group of novel factors involved in DNA repair. In this review, we integrate some of these datasets to identify commonalities that might highlight novel and interesting factors for future investigations. This emerging role for RNA opens up a new dimension in the field of DNA repair; we discuss its impact on our current understanding of DNA repair processes and consider how it might influence cancer progression.

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“…Therefore, more studies are required to unravel the exact role and interplay between BER and NER proteins in the repair process of cisplatin induced DNA damage. Slyskova et al (2018) recently used a CRISPR/Cas9 screen to determine which proteins and pathways are involved in the repair of oxaliplatin and cisplatin induced ad-ducts. These drugs covalently bind to DNA and form crosslinks, mainly Pt-GpG (60-65%) and Pt-ApG (25-30%), along with monoadducts (2%).…”

Section: Protein-protein Interaction Referencesmentioning

confidence: 99%

Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

et al. 2020

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Base and nucleotide excision repair (BER and NER) pathways are normally associated with removal of specific types of DNA damage: small base modifications (such as those induced by DNA oxidation) and bulky DNA lesions (such as those induced by ultraviolet or chemical carcinogens), respectively. However, growing evidence indicates that this scenario is much more complex and these pathways exchange proteins and cooperate with each other in the repair of specific lesions. In this review, we highlight studies discussing the involvement of NER in the repair of DNA damage induced by oxidative stress, and BER participating in the removal of bulky adducts on DNA. Adding to this complexity, UVA light experiments revealed that oxidative stress also causes protein oxidation, directly affecting proteins involved in both NER and BER. This reduces the cell's ability to repair DNA damage with deleterious implications to the cells, such as mutagenesis and cell death, and to the organisms, such as cancer and aging. Finally, an interactome of NER and BER proteins is presented, showing the strong connection between these pathways, indicating that further investigation may reveal new functions shared by them, and their cooperation in maintaining genome stability.

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Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage

Cited by 85 publications

References 85 publications

Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer

The roles of RNA in DNA double-strand break repair

Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

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