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Mutation in DNA Polymerase Beta Causes Spontaneous Chromosomal Instability and Inflammation-Associated Carcinogenesis in Mice

1
Division 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
2
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Cancers 2019, 11(8), 1160; https://doi.org/10.3390/cancers11081160
Received: 14 June 2019 / Revised: 1 August 2019 / Accepted: 8 August 2019 / Published: 13 August 2019
(This article belongs to the Special Issue Recent Advances in Gastric Cancer)
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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. View Full-Text
Keywords: DNA polymerase beta; mutation; genomic instability; inflammation DNA polymerase beta; mutation; genomic instability; inflammation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Zhao, S.; Klattenhoff, A.W.; Thakur, M.; Sebastian, M.; Kidane, D. Mutation in DNA Polymerase Beta Causes Spontaneous Chromosomal Instability and Inflammation-Associated Carcinogenesis in Mice. Cancers 2019, 11, 1160.

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