Gastric cancer is a global health problem with a high rate of tumor incidence and mortality. Environmental and genetic factors are both important to promote genomic instability and possibly gastric carcinogenesis. The maintenance of genome integrity is dependent on numerous mechanisms, which notably allow fidelity of DNA replication and repair of damaged DNA. Those processes require a large number of proteins including DNA polymerase beta (Pol ?). Pol ? is a key enzyme for the protection of oxidative DNA lesions via its role in base excision repair (BER). Approximately 30% of tumors studied to date express Pol ? variant proteins, and several tumors over express Pol ?. If Pol ? becomes defective, DNA damage will be left resulting in genomic instability. Genomic instability occurs in two different pathways, one resulting in an increased mutation rate at the nucleotide level and the other corresponding to chromosomal instability leading to abnormal chromosome numbers or rearrangement. Direct sequencing of the PolB gene from different cancer cells identified a number of mutations including L22P gastric cancer associated variant of Pol ? (dRP lyase deficient). It is well documented that dRP lyase activity of Pol ? protect cells from cytotoxicity of alkylating agents. Data showing that L22P lacks dRP lyase and has less DNA-binding affinity are consistent with the possibility that this variant is linked to human cancer. In order to further our understanding of the biological consequences of L22P in BER and, in particular, the effect of L22P expression on DNA repair fidelity as well as chromosomal stability, we will assess genomic instability after expressing L22P variant of Pol ?. The goal of this study is to determine whether the L22P gastric cancer-associated Pol ? variant induces genomic instability and promotes tumorigenesis. Specifically, we will focus to answer how L22P induces genomic instability using mutagenesis and chromosomal aberration studies. To achieve our objective, we will construct L22P conditional knock-in transgenic mice and characterize spontaneous tumorigenesis as well as host genetic predisposition after Helicobacter infection. This project will help to get mechanistic data that could promote our basic understanding of the host genetic factors and environmental stimuli to accelerate initiation or progression of gastric cancer.

Public Health Relevance

Gastric cancer is a global health problem, and accumulation of mutations in cells can lead to the onset of cancer. By studying the ways in which cells create, prevent and correct mutations, a greater understanding of this disease can be achieved. ) The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Subcommittee G - Education (NCI)
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Ojeifo, John O
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Yale University
Schools of Medicine
New Haven
United States
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Kidane, Dawit; Chae, Wook Jin; Czochor, Jennifer et al. (2014) Interplay between DNA repair and inflammation, and the link to cancer. Crit Rev Biochem Mol Biol 49:116-39
Kidane, D; Murphy, D L; Sweasy, J B (2014) Accumulation of abasic sites induces genomic instability in normal human gastric epithelial cells during Helicobacter pylori infection. Oncogenesis 3:e128
Kidane, Dawit; Sakkas, Denny; Nottoli, Timothy et al. (2013) Kinesin 5B (KIF5B) is required for progression through female meiosis and proper chromosomal segregation in mitotic cells. PLoS One 8:e58585
Kidane, Dawit; Ayora, Silvia; Sweasy, Joann B et al. (2012) The cell pole: the site of cross talk between the DNA uptake and genetic recombination machinery. Crit Rev Biochem Mol Biol 47:531-55
Kidane, Dawit; Sweasy, Joann B (2012) Tipping the balance in the powerhouse of the cell to ""protect"" colorectal cancer. PLoS Genet 8:e1002758