Mechanism of action of nucleotide excision repair machinery

D’Souza, Areetha; Blee, Alexandra M.; Chazin, Walter

doi:10.1042/bst20210246

Cited by 16 publications

(8 citation statements)

References 140 publications

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“…As a NER scaffold protein, XPA interacts with many other NER factors as well as RPA and the DNA near a lesion, all of which are required to assemble the catalytically competent incision complex ( 51 ). Therefore, recruitment of XPA to the damaged site is integral to successful repair.…”

Section: Resultsmentioning

confidence: 99%

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin

Blee,

Gallagher,

Kim

et al. 2024

NAR Cancer

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Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (ERCC1 and ERCC2) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including in vitro analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.

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Section: Resultsmentioning

confidence: 99%

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin

Blee,

Gallagher,

Kim

et al. 2024

NAR Cancer

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“…Since our data indicate a sequence preference for the 5′ incision by XPF-ERCC1 (Figure 4 ), which is known to occur first in the NER reaction ( 15 , 25 ), we wondered to what extent the location of the 5′ incision event affects overall fragment length. To address this question, we compared 5′ incision site distance and fragment length in published human CPD XR-seq reads ( 31 ) containing tandem CC > TT mismatches, since these tandem mismatches precisely specify the location of the CPD lesion.…”

Section: Resultsmentioning

confidence: 99%

“…It is also unclear whether these in vitro findings can explain variations in NER fragment length and incision site choice in vivo . Finally, whether the location of the 5′ incision, which occurs first during NER ( 15 , 25 ), influences subsequent 3′ incision site choice is unknown.…”

Section: Introductionmentioning

confidence: 99%

Analysis of cytosine deamination events in excision repair sequencing reads reveals mechanisms of incision site selection in NER

Morledge-Hampton,

Kalyanaraman,

Wyrick

2023

Nucleic Acids Research

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Nucleotide excision repair (NER) removes helix-distorting DNA lesions and is therefore critical for genome stability. During NER, DNA is unwound on either side of the lesion and excised, but the rules governing incision site selection, particularly in eukaryotic cells, are unclear. Excision repair-sequencing (XR-seq) sequences excised NER fragments, but analysis has been limited because the lesion location is unknown. Here, we exploit accelerated cytosine deamination rates in UV-induced CPD (cyclobutane pyrimidine dimer) lesions to precisely map their locations at C to T mismatches in XR-seq reads, revealing general and species-specific patterns of incision site selection during NER. Our data indicate that the 5′ incision site occurs preferentially in HYV (i.e. not G; C/T; not T) sequence motifs, a pattern that can be explained by sequence preferences of the XPF-ERCC1 endonuclease. In contrast, the 3′ incision site does not show strong sequence preferences, once truncated reads arising from mispriming events are excluded. Instead, the 3′ incision is partially determined by the 5′ incision site distance, indicating that the two incision events are coupled. Finally, our data reveal unique and coupled NER incision patterns at nucleosome boundaries. These findings reveal key principles governing NER incision site selection in eukaryotic cells.

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“…Similarly, unique DAMs in Zm also reduced the enrichment of the Nucleotide excision repair pathway ( Figure 7C ). In order to protect themselves from the severe consequences of DNA damage from multiple sources such as UV irradiation and environmental toxins, cells have evolved a multifunctional Nucleotide excision repair pathway, and this pathway has been found to be one of the major pathways for rhizosphere enrichment in continuous cropping peanuts ( Li et al, 2018 ; Kraithong et al, 2021 ; D’souza et al, 2022 ). Streptomycin is commonly used as antibiotic which inhibits soil-borne pathogens to a large extent ( Liu et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Diversity and correlation analysis of different root exudates on the regulation of microbial structure and function in soil planted with Panax notoginseng

Shi,

Yang,

et al. 2023

Front. Microbiol.

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IntroductionSpecific interactions between root exudates and soil microorganisms has been proposed as one of the reasons accounting for the continuous cropping obstacle (CCO) of Panax notoginseng. However, rotation of other crops on soils planted with P. notoginseng (SPP) did not show CCO, suggesting that root exudates of different crops differentially regulate soil microorganisms in SPP.MethodsHere, we investigated the microbial community structure and specific interaction mechanisms of the root exudates of the four plant species, P. notoginseng (Pn), Zea mays (Zm), Nicotiana tabacum (Nt) and Perilla frutescens (Pf), in SPP by static soil culture experiment.ResultsThe results showed that the chemical diversity of root exudates varied significantly among the four plant species. Pn had the highest number of unique root exudates, followed by Nt, Zm and Pf. Terpenoids, flavonoids, alkaloids and phenolic acids were the most abundant differentially accumulated metabolites (DAMs) in Pn, Nt, Zm and Pf, respectively. However, lipids were the most abundant common DAMs among Zm Nt and Pf. Pn root exudates decreased the relative abundance of bacteria, but increased that of fungi. While specific DAMs in Pn enriched Phenylobacterium_zucineum, Sphingobium_yanoikuyae, Ophiostoma_ulmi and functional pathways of Nucleotide excision repair, Streptomycin biosynthesis, Cell cycle-Caulobacter and Glycolysis/Gluconeogenesis, it inhibited Paraburkholderia _caledonica and Ralstonia_pickettii. However, common DAMs in Zm, Nt and Pf had opposite effects. Moreover, common DAMs in Zm, Nt and Pf enriched Ralstonia_pseudosolanacearum and functional pathway of Xylene degradation; unique DAMs in Zm enriched Talaromyces_purcureogeneus, while inhibiting Fusarium_tricinctum and functional pathways of Nucleotide excision repair and Alanine, aspartate and glutamate metabolism; unique DAMs in Pf enriched Synchytrium_taraxaci.DiscussionThe core strains identified that interact with different root exudates will provide key clues for regulation of soil microorganisms in P. notoginseng cultivation to alleviate CCO.

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Mechanism of action of nucleotide excision repair machinery

Cited by 16 publications

References 140 publications

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin

Analysis of cytosine deamination events in excision repair sequencing reads reveals mechanisms of incision site selection in NER

Diversity and correlation analysis of different root exudates on the regulation of microbial structure and function in soil planted with Panax notoginseng

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