Mutation in dna polymerase beta causes spontaneous chromosomal instability and inflammation-associated carcinogenesis in mice

Shengyuan Zhao, Alex W. Klattenho, Megha Thakur, Manu Sebastian, Dawit Kidane

Research output: Contribution to journalArticle

Abstract

DNA polymerase beta (Pol β) is a key enzyme in the base excision repair (BER) pathway. Pol β is mutated in approximately 40% of human tumors in small-scale studies. The 5´-deoxyribose-5-phosphate (dRP) lyase domain of Pol β is responsible for DNA end tailoring to remove the 5’ phosphate group. We previously reported that the dRP lyase activity of Pol β is critical to maintain DNA replication fork stability and prevent cellular transformation. In this study, we tested the hypothesis that the human gastric cancer associated variant of Pol β (L22P) has the ability to promote spontaneous chromosomal instability and carcinogenesis in mice. We constructed a Pol β L22P conditional knock-in mouse model and found that L22P enhances hyperproliferation and DNA double strand breaks (DSBs) in stomach cells. Moreover, mouse embryonic fibroblasts (MEFs) derived from L22P mice frequently induce abnormal numbers of chromosomes and centrosome amplification, leading to chromosome segregation errors. Importantly, L22P mice exhibit chronic inflammation accompanied by stomach tumors. These data demonstrate that the human cancer-associated variant of Pol β can contribute to chromosomal instability and cancer development.

Original languageEnglish (US)
Article number1160
JournalCancers
Volume11
Issue number8
DOIs
StatePublished - Aug 2019

Fingerprint

Chromosomal Instability
Carcinogenesis
Inflammation
Mutation
Neoplasms
Stomach
DNA Polymerase beta
Centrosome
Chromosome Segregation
Double-Stranded DNA Breaks
DNA Replication
DNA Repair
Stomach Neoplasms
Fibroblasts
Chromosomes
Phosphates
DNA
Enzymes

Keywords

  • DNA polymerase beta
  • Genomic instability
  • Inflammation
  • Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mutation in dna polymerase beta causes spontaneous chromosomal instability and inflammation-associated carcinogenesis in mice. / Zhao, Shengyuan; Klattenho, Alex W.; Thakur, Megha; Sebastian, Manu; Kidane, Dawit.

In: Cancers, Vol. 11, No. 8, 1160, 08.2019.

Research output: Contribution to journalArticle

Zhao, Shengyuan ; Klattenho, Alex W. ; Thakur, Megha ; Sebastian, Manu ; Kidane, Dawit. / Mutation in dna polymerase beta causes spontaneous chromosomal instability and inflammation-associated carcinogenesis in mice. In: Cancers. 2019 ; Vol. 11, No. 8.
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