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Mechanisms for the repair of oxidative stress-induced DNA damage in Porphyromonas

Mechanisms for the repair of oxidative stress-induced DNA damage in Porphyromonas
卟啉单胞菌氧化应激诱导的 DNA 损伤的修复机制
批准号:
10441150
负责人:
Hansel M. Fletcher
金额:
$19.75万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-07-01 至 2023-06-30

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中文摘要
翻译
牙龈卟啉单胞菌作为一种“关键病原体”,突出了其适应严酷炎症的能力
英文摘要
Porphyromonas gingivalis, as a “keystone pathogen”, highlights its ability to adapt to the harsh inflammatory conditions of the periodontal pocket. Because the environmental stress response is a major determinant of its virulence, it is our long-term goal to gain a comprehensive understanding of its survival strategy(s). DNA damage is a major consequence of oxidative stress. While more than 20 different oxidatively altered bases might be generated by this stress, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most common product of DNA damage. Guanine is the most susceptible base to oxidation and forms mainly 8-oxoG due to its low redox potential. In prokaryotic cells the presence of 8-oxoG is mainly repaired by base excision repair (BER). A survey of the P. gingivalis genome indicate that an important component of the BER system is missing. Because the average G + C content of the genome of P. gingivalis is 49%, a mechanism(s) to prevent or repair lesions resulting from guanine oxidation is vital. There is a gap in our comprehensive knowledge on a mechanism(s) for the repair of oxidative stress-induced DNA damage in P. gingivalis. We have previously demonstrated that there is an accumulation of 8-oxoG in the chromosome of P. gingivalis exposed to H2O2-induced oxidative stress. Neither BER nor nucleotide excision repair (NER), as observed in other strains, appear to be involved in the repair of the 8-oxoG lesion in P. gingivalis. DNA affinity fractionation identified PG1037, a conserved hypothetical protein, among others, that were preferentially bound to the oligonucleotide fragment carrying the 8-oxo-G lesion. PG1037 is part of the uvrA-pg1037-pcrA operon in P. gingivalis which is known to be upregulated under H2O2- induced stress. The purified recombinant PG1037 protein, likely via a reducing function, has the ability to prevent Fenton chemistry-mediated DNA damage in vitro and, under oxidative stress conditions, reduced the cleavage of the 8-oxoG lesion by the E.coli foramidopyrimidine glycosylase (Fpg) enzyme. In silico analysis of PG1037 shows a protein that contains a zinc finger domain, two peroxidase homologous motifs and a cytidylate kinase domain. The goal of the proposal is to test the hypothesis that a novel P. gingivalis protein (PG1037) carrying peroxidase motifs and a zinc finger domain is involved in the repair of oxidatively damaged DNA. Our aims are to confirm the specific role of PG1037 in the removal of 8-oxoG from duplex DNA and to evaluate any interaction of PG1037 with other proteins in that process. The data will provide a major conceptual advance on the molecular bases for the repair of oxidative stress-induced DNA damage in P. gingivalis and could likely support a unique and effective DNA repair mechanism we propose to designate “base redox repair”. It will set the stage, in a future RO1 application, to address specific structure-function questions on the vital components and their corporation in maintaining genomic stability in anaerobes exposed to environmental stress. These components could be targets for the development of novel therapeutic interventions for the control and prevention of P. gingivalis-associated diseases.
期刊论文(7)
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会议论文
DOI: 10.1371/journal.pone.0290845
发表时间: 2023
期刊: PloS one
影响因子: 3.7
作者: []
通讯作者:
DOI: 10.1128/spectrum.01212-21
发表时间: 2021-12-22
期刊: Microbiology spectrum
影响因子: 3.7
作者: [Aja E, Mishra A, Dou Y, Fletcher HM]
通讯作者: Fletcher HM
DOI: 10.1111/omi.12362
发表时间: 2022-04
期刊: MOLECULAR ORAL MICROBIOLOGY
影响因子: 3.7
作者: [Natto, Zuhair S., Afeef, Marwah, Bakhrebah, Muhammed A., Ashi, Heba, Alzahrani, Khaled A., Alhetheel, Abdulkarim F., Fletcher, Hansel M.]
通讯作者: Fletcher, Hansel M.
DOI: 10.3390/cancers14122874
发表时间: 2022-06-10
期刊: CANCERS
影响因子: 5.2
作者: [Li, Xin, Wang, Xiaoqi, Huang, Ruihao, Stucky, Andres, Chen, Xuelian, Sun, Lan, Wen, Qin, Zeng, Yunjing, Fletcher, Hansel, Wang, Charles, Xu, Yi, Cao, Huynh, Sun, Fengzhu, Li, Shengwen Calvin, Zhang, Xi, Zhong, Jiang]
通讯作者: Zhong, Jiang
6
    Studies on the virulence regulation in Porphyromonas
    • 批准号:
      9079134
    • 项目类别:
    • 资助金额:
      $40.87万
    • 财政年份:
      2016
    • 负责人:
      Hansel M. Fletcher
    • 依托单位:
    Studies on the virulence regulation in Porphyromonas
    • 批准号:
      9888964
    • 项目类别:
    • 资助金额:
      $39.42万
    • 财政年份:
      2016
    • 负责人:
      Hansel M. Fletcher
    • 依托单位:
    ECF sigma factors in adaptation and virulence of Porphyromonas gingivalis
    • 批准号:
      8513305
    • 项目类别:
    • 资助金额:
      $34.13万
    • 财政年份:
      2012
    • 负责人:
      Hansel M. Fletcher
    • 依托单位:
    Studies on the virulence of Fillifactor alocis
    • 批准号:
      8467702
    • 项目类别:
    • 资助金额:
      $18.96万
    • 财政年份:
      2012
    • 负责人:
      Hansel M. Fletcher
    • 依托单位:
    海外基金