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<p>Periodontitis is a multifactorial inflammatory condition that results in the gradual loss of the supporting tissues of the teeth. Studies have elucidated that DNA damage response (DDR) pathways may be an important regulator in the pathogenesis of periodontal disease. Periodontal pathogens such as <i>Porphyromonas gingivalis</i> induce oxidative stress, leading to the activation of the DDR, which amplifies tissue damage, and permits pathogens to circumvent the host immune response via hijacked host DDR machineries for perpetuated immune-inflammatory mechanisms. In this review, the interaction between these three players, with particular focus on the molecular mechanisms linking DDR, oxidative stress, and microbial dysbiosis in periodontitis is presented along with suggestion of novel therapeutic targets aimed at modulating these pathways. The DDR machinery processes genomic instability and its consequences through key molecules (ATM, ATR, PARP1, and the MRN complex). However, DDR expression is activated during chronic inflammation, suggesting that it constitutes a pathogenic feedback loop that exacerbates tissue injury. This review is structured into three parts: (1) intercellular and cell-environmental crosstalk, encouraging oxidative stress, DDR response, and tissue damage; (2) DDR-SASP sub-axis, leading to chronic inflammation in sensitizing senescent cells; and (3) bacterial mechanisms in regulating DDR transport. Such targets  have been considered appealing in research focused on therapeutics, such as epigenetic regulators, senolytics, or DDR modulators. Clinical  trial results using such strategies have shown that these methods may be efficient, particularly when combination therapies can be used. Such an overview can provide comprehensive framework to understand the relevance of DDR to periodontal diseases while simultaneously delineating therapeutic opportunities for precision medicine approaches to treating periodontitis.</p>

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Molecular basis of DNA damage response (DDR) pathway in periodontitis: pathogenic mechanisms and therapeutic directions

  • 期刊论文

  • 发表日期：

    2025年5月13日

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  • Saravanan Sampoornam Pape Reddy,
  • Delfin Lovelina Francis,
  • Anitha Logaranjani,
  • Anirudha Agnihotry,
  • Shaili Pradhan,
  • Sukumaran Anil

摘要

Periodontitis is a multifactorial inflammatory condition that results in the gradual loss of the supporting tissues of the teeth. Studies have elucidated that DNA damage response (DDR) pathways may be an important regulator in the pathogenesis of periodontal disease. Periodontal pathogens such as Porphyromonas gingivalis induce oxidative stress, leading to the activation of the DDR, which amplifies tissue damage, and permits pathogens to circumvent the host immune response via hijacked host DDR machineries for perpetuated immune-inflammatory mechanisms. In this review, the interaction between these three players, with particular focus on the molecular mechanisms linking DDR, oxidative stress, and microbial dysbiosis in periodontitis is presented along with suggestion of novel therapeutic targets aimed at modulating these pathways. The DDR machinery processes genomic instability and its consequences through key molecules (ATM, ATR, PARP1, and the MRN complex). However, DDR expression is activated during chronic inflammation, suggesting that it constitutes a pathogenic feedback loop that exacerbates tissue injury. This review is structured into three parts: (1) intercellular and cell-environmental crosstalk, encouraging oxidative stress, DDR response, and tissue damage; (2) DDR-SASP sub-axis, leading to chronic inflammation in sensitizing senescent cells; and (3) bacterial mechanisms in regulating DDR transport. Such targets  have been considered appealing in research focused on therapeutics, such as epigenetic regulators, senolytics, or DDR modulators. Clinical  trial results using such strategies have shown that these methods may be efficient, particularly when combination therapies can be used. Such an overview can provide comprehensive framework to understand the relevance of DDR to periodontal diseases while simultaneously delineating therapeutic opportunities for precision medicine approaches to treating periodontitis.