Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice
<i>H. pylori</i> is a significant risk factor of gastric cancer that induces chronic inflammation and oxidative DNA damage to promote gastric carcinoma. Base excision repair (BER) is required to maintain the genome integrity and prevent oxidative DNA damage. Mutation in DNA polymerase be...
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MDPI AG
2019-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/6/843 |
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| author | Shengyuan Zhao Megha Thakur Alex W. Klattenhoff Dawit Kidane |
| author_facet | Shengyuan Zhao Megha Thakur Alex W. Klattenhoff Dawit Kidane |
| author_sort | Shengyuan Zhao |
| collection | DOAJ |
| description | <i>H. pylori</i> is a significant risk factor of gastric cancer that induces chronic inflammation and oxidative DNA damage to promote gastric carcinoma. Base excision repair (BER) is required to maintain the genome integrity and prevent oxidative DNA damage. Mutation in DNA polymerase beta (Pol β) impacts BER efficiency and has been reported in approximately 30−40% of gastric carcinoma tumors. In this study, we examined whether reduced BER capacity associated with mutation in the <i>POLB</i> gene, along with increased DNA damage generated by <i>H. pylori</i> infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with <i>H. pylori</i>, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, <i>H. pylori</i> infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated <i>H. pylori</i> induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of <i>H. pylori</i> induced stomach carcinogenesis. |
| first_indexed | 2024-03-12T19:19:28Z |
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| id | doaj.art-fb59cd948b10407ca42375c52cb24261 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T19:19:28Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fb59cd948b10407ca42375c52cb242612023-08-02T05:19:54ZengMDPI AGCancers2072-66942019-06-0111684310.3390/cancers11060843cancers11060843Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in MiceShengyuan Zhao0Megha Thakur1Alex W. Klattenhoff2Dawit Kidane3Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Blvd. R1800, Austin, TX 78723, USADivision of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Blvd. R1800, Austin, TX 78723, USADivision of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Blvd. R1800, Austin, TX 78723, USADivision of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Blvd. R1800, Austin, TX 78723, USA<i>H. pylori</i> is a significant risk factor of gastric cancer that induces chronic inflammation and oxidative DNA damage to promote gastric carcinoma. Base excision repair (BER) is required to maintain the genome integrity and prevent oxidative DNA damage. Mutation in DNA polymerase beta (Pol β) impacts BER efficiency and has been reported in approximately 30−40% of gastric carcinoma tumors. In this study, we examined whether reduced BER capacity associated with mutation in the <i>POLB</i> gene, along with increased DNA damage generated by <i>H. pylori</i> infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with <i>H. pylori</i>, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, <i>H. pylori</i> infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated <i>H. pylori</i> induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of <i>H. pylori</i> induced stomach carcinogenesis.https://www.mdpi.com/2072-6694/11/6/843mutation in DNA polymerase betagenomic instability<i>H. pylori</i>gastric cancer |
| spellingShingle | Shengyuan Zhao Megha Thakur Alex W. Klattenhoff Dawit Kidane Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice Cancers mutation in DNA polymerase beta genomic instability <i>H. pylori</i> gastric cancer |
| title | Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice |
| title_full | Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice |
| title_fullStr | Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice |
| title_full_unstemmed | Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice |
| title_short | Aberrant DNA Polymerase Beta Enhances <i>H. pylori</i> Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice |
| title_sort | aberrant dna polymerase beta enhances i h pylori i infection induced genomic instability and gastric carcinogenesis in mice |
| topic | mutation in DNA polymerase beta genomic instability <i>H. pylori</i> gastric cancer |
| url | https://www.mdpi.com/2072-6694/11/6/843 |
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