Journal of Microbiology

Journal Article

GABA-producing Lactobacillus plantarum inhibits metastatic properties and induces apoptosis of 5-FU-resistant colorectal cancer cells via GABAB receptor signaling: JaeJin An , Heon Seok , Eun-Mi Ha; J. Microbiol. 2021;59(2):202-216. Published online February 1, 2021; DOI: https://doi.org/10.1007/s12275-021-0562-5

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5-Fluorouracil (5-FU) is an essential drug in systemic chemotherapy treatments for colorectal cancer (CRC). Despite the development of several treatment strategies over the past decades, the patient benefits of 5-FU-based therapies have been compromised by the development of chemoresistance. Differences in treatment responses among CRC patients may be due to genetic and epigenetic factors unique to individuals. Therefore, important factors for realizing personalized medicine are to accurately understand the causes and mechanisms of drug resistance to 5-FU-based therapies and to identify and validate prognostic biomarkers. Gut microbes that interact directly with the host contribute to human health and cancer control. Lactobacillus plantarum, in particular, has the potential to be a therapeutic agent by producing bioactive compounds that may benefit the host. Here, we investigated the gamma-aminobutyric acid (GABA) and GABAB receptor (GABABR)-dependent signaling pathway as a treatment option for 5-FU-resistant HT-29 cells. GABA-producing L. plantarum activates anti-proliferative, anti-migration, and anti-invasion effects against 5-FU-resistant HT-29 cells. The inhibitory effects of GABA-producing L. plantarum are mediated via GABABR. Activated GABABR induces apoptosis through the inhibition of cAMP-dependent signaling pathways and cellular inhibitor of apoptosis protein 2 (cIAP2) expression. Thus, the GABAergic system has potential in 5- FU-resistant HT-29 cells as a predictive biomarker. In addition, GABA-producing L. plantarum is promising as an adjuvant treatment for 5-FU-resistant CRC, and its intervention in neurobiological signaling imply new possibilities for chemoprevention and the treatment of colon cancer-related diseases.

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Review

MINIREVIEW] Synthetic lethal interaction between oxidative stress response and DNA damage repair in the budding yeast and its application to targeted anticancer therapy: Ji Eun Choi , Woo-Hyun Chung; J. Microbiol. 2019;57(1):9-17. Published online December 29, 2018; DOI: https://doi.org/10.1007/s12275-019-8475-2

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Abstract

Synthetic lethality is an extreme form of negative genetic epistasis that arises when a combination of functional deficiency in two or more genes results in cell death, whereas none of the single genetic perturbations are lethal by themselves. This unconventional genetic interaction is a modification of the concept of essentiality that can be exploited for the purpose of targeted cancer therapy. The yeast Saccharomyces cerevisiae has been pivotally used for early large-scale synthetic lethal screens due to its experimental advantages, but recent advances in gene silencing technology have now made direct high-throughput analysis possible in higher organisms. Identification of tumor-specific alterations and characterization of the mechanistic principles underlying synthetic lethal interaction are the key to applying synthetic lethality to clinical cancer treatment by enabling genome-driven oncological research. Here, we provide emerging ideas on the synthetic lethal interactions in budding yeast, particularly between cellular processes responsible for oxidative stress response and DNA damage repair, and discuss how they can be appropriately utilized for context-dependent cancer therapeutics.

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Journal Article

Isolation of Synthetic Lethal Mutations in the rsm1-null Mutant of Fission Yeast: DongGeRaMi Moon , Yun-Sun Park , Cha-Yeon Kim , Jin Ho Yoon; J. Microbiol. 2010;48(5):701-705. Published online November 3, 2010; DOI: https://doi.org/10.1007/s12275-010-0353-x

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Abstract: To identify mutations in genes that are genetically linked to rsm1, we performed a synthetic lethal genetic screen in the fission yeast, Schizosaccharomyces pombe. Four mutations that showed synthetic lethality in combination with the rsm1null allele were isolated from approximately 320,000 colonies and defined in three complementation groups. One mutant (SLrsm1) exhibited a significant accumulation of poly(A)+ RNA in the nucleus under synthetic lethal conditions, while the rest had no mRNA export defects. In addition, some genes (spmex67, rae1, or mlo3) required for mRNA export complemented the growth defects of the identified mutants. These results suggest that the isolated mutants contain mutations in genes that are involved in mRNA export and/or pre-mRNA retention.

Research Support, Non-U.S. Gov't

Schizosaccharomyces pombe nup97, which Genetically Interacts with mex67, is Essential for Growth and Involved in mRNA Export: Hyun Jin Cho , Duk Kyung Hwang , Sun Im Jung , Jin Ho Yoon; J. Microbiol. 2007;45(4):344-349.; DOI: https://doi.org/2562 [pii]

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Abstract: We have isolated previously three synthetic lethal mutants in Schizosaccharomyces pombe, which genetically interact with mex67, in order to identify the genes involved in mRNA export. A novel nup97 gene was isolated by complementation of the growth defect in one of the synthetic lethal mutants, SLMex3. The nup97 gene contains one intron and encodes an 851 amino-acid protein that is similar to nucleoporins, Npp106p in S. pombe and Nic96p in Saccharomyces cerevisiae. The nup97 gene is essential for vegetative growth, and nup97 null mutant harboring pREP41X-Nup97 showed poly(A)+ RNA export defect when expression of nup97 is repressed in the presence of thiamine. These results suggest that nup97 is involved in mRNA export from the nucleus to cytoplasm.

Journal Article

Schizosaccharomyces pombe rsm1 Genetically Interacts with spmex67, Which Is Involved in mRNA Export: Jin Ho Yoon; J. Microbiol. 2004;42(1):32-36.; DOI: https://doi.org/2004 [pii]

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Abstract: We have previously isolated three synthetic lethal mutants from Schizosaccharomyces pombe in order to identify mutations in the genes that are functionally linked to spmex67 with respect to mRNA export. A novel rsm1 gene was isolated by complementation of the growth defect in one of the synthetic lethal mutants, SLMex1. The rsm1 gene contains no introns and encodes a 296 amino-acid-long protein with the RING finger domain, a C3HC4 in the N-terminal half. The [delta]rsm1 null mutant is viable, but it showed a slight poly(A)^+ RNA accumulation in the nucleus. Also, the combination of [delta]rsm1 and [delta]spmex67 mutations confers synthetic lethality that is accompanied by the severe poly(A)^+ RNA export defect. These results suggest that rsm1 is involved in mRNA export from the nucleus.

Synthetic Lethal Mutations with spmex67 of Schizosaccharomyces pombe in the Mediation of mRNA Export: Jin Ho Yoon; J. Microbiol. 2003;41(2):115-120.

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Abstract: Mex67p/Tap are evolutionally conserved mRNA export factors. To identify mutations in genes that are functionally linked to mex67 with respect to mRNA export, we used a synthetic lethal genetic screen in Schizosaccharomyces pombe. Three synthetic lethal mutants were isolated and mutations in these mutants defined separate complementation groups. These mutants exhibited the accumulation of poly(A)^+ RNA in the nucleus, with a decrease in the cytoplasm under synthetically lethal conditions, suggesting that the mutations cause an mRNA nuclear export defect. In addition, the S. pombe genes that were found to be involved in mRNA export did not suppress the synthetic lethality of these mutants. These results indicate that the isolated mutants contain mutations in new genes, which are involved in mRNA export from the nucleus.

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