Aberrant DNA polymerase beta enhances H. Pylori infection induced genomic instability and gastric carcinogenesis in mice

Shengyuan Zhao, Megha Thakur, Alex W. Klattenhoff, Dawit Kidane

Research output: Contribution to journalArticle

Abstract

H. pylori 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 POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.

Original languageEnglish (US)
Article number843
JournalCancers
Volume11
Issue number6
DOIs
StatePublished - Jun 2019

Fingerprint

DNA Polymerase beta
Genomic Instability
Pylorus
Stomach
Carcinogenesis
DNA Repair
DNA Damage
Infection
Inflammation
Stomach Neoplasms
Carcinoma
Reactive Nitrogen Species
Mutation
Reactive Oxygen Species
Neoplasms
Nitric Oxide
Genome
Incidence
Genes

Keywords

  • Gastric cancer
  • Genomic instability
  • H. pylori
  • Mutation in DNA polymerase beta

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aberrant DNA polymerase beta enhances H. Pylori infection induced genomic instability and gastric carcinogenesis in mice. / Zhao, Shengyuan; Thakur, Megha; Klattenhoff, Alex W.; Kidane, Dawit.

In: Cancers, Vol. 11, No. 6, 843, 06.2019.

Research output: Contribution to journalArticle

@article{1c978a9b3e9c47de9ab06e192928136e,
title = "Aberrant DNA polymerase beta enhances H. Pylori infection induced genomic instability and gastric carcinogenesis in mice",
abstract = "H. pylori 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 POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.",
keywords = "Gastric cancer, Genomic instability, H. pylori, Mutation in DNA polymerase beta",
author = "Shengyuan Zhao and Megha Thakur and Klattenhoff, {Alex W.} and Dawit Kidane",
year = "2019",
month = "6",
doi = "10.3390/cancers11060843",
language = "English (US)",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "6",

}

TY - JOUR

T1 - Aberrant DNA polymerase beta enhances H. Pylori infection induced genomic instability and gastric carcinogenesis in mice

AU - Zhao, Shengyuan

AU - Thakur, Megha

AU - Klattenhoff, Alex W.

AU - Kidane, Dawit

PY - 2019/6

Y1 - 2019/6

N2 - H. pylori 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 POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.

AB - H. pylori 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 POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.

KW - Gastric cancer

KW - Genomic instability

KW - H. pylori

KW - Mutation in DNA polymerase beta

UR - http://www.scopus.com/inward/record.url?scp=85070619691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070619691&partnerID=8YFLogxK

U2 - 10.3390/cancers11060843

DO - 10.3390/cancers11060843

M3 - Article

AN - SCOPUS:85070619691

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 6

M1 - 843

ER -