- Signification and Application of Mutator and Antimutator Phenotype‑Induced Genetic Variations in Evolutionary Adaptation and Cancer Therapeutics
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Woo-Hyun Chung
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J. Microbiol. 2023;61(12):1013-1024. Published online December 15, 2023
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DOI: https://doi.org/10.1007/s12275-023-00091-z
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Mutations present a dichotomy in their implications for cellular processes. They primarily arise from DNA replication errors
or damage repair processes induced by environmental challenges. Cumulative mutations underlie genetic variations and
drive evolution, yet also contribute to degenerative diseases such as cancer and aging. The mutator phenotype elucidates the
heightened mutation rates observed in malignant tumors. Evolutionary adaptation, analogous to bacterial and eukaryotic
systems, manifests through mutator phenotypes during changing environmental conditions, highlighting the delicate balance
between advantageous mutations and their potentially detrimental consequences. Leveraging the genetic tractability
of Saccharomyces cerevisiae offers unique insights into mutator phenotypes and genome instability akin to human cancers.
Innovative reporter assays in yeast model organisms enable the detection of diverse genome alterations, aiding a comprehensive
analysis of mutator phenotypes. Despite significant advancements, our understanding of the intricate mechanisms
governing spontaneous mutation rates and preserving genetic integrity remains incomplete. This review outlines various
cellular pathways affecting mutation rates and explores the role of mutator genes and mutation-derived phenotypes, particularly
prevalent in malignant tumor cells. An in-depth comprehension of mutator and antimutator activities in yeast and
higher eukaryotes holds promise for effective cancer control strategies.
- Functional interplay between the oxidative stress response and DNA damage checkpoint signaling for genome maintenance in aerobic organisms
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Ji Eun Choi , Woo-Hyun Chung
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J. Microbiol. 2020;58(2):81-91. Published online December 23, 2019
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DOI: https://doi.org/10.1007/s12275-020-9520-x
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The DNA damage checkpoint signaling pathway is a highly
conserved surveillance mechanism that ensures genome integrity
by sequential activation of protein kinase cascades.
In mammals, the main pathway is orchestrated by two central
sensor kinases, ATM and ATR, that are activated in response
to DNA damage and DNA replication stress. Patients
lacking functional ATM or ATR suffer from ataxia-telangiectasia
(A-T) or Seckel syndrome, respectively, with pleiotropic
degenerative phenotypes. In addition to DNA strand
breaks, ATM and ATR also respond to oxidative DNA damage
and reactive oxygen species (ROS), suggesting an unconventional
function as regulators of intracellular redox status.
Here, we summarize the multiple roles of ATM and ATR, and
of their orthologs in Saccharomyces cerevisiae, Tel1 and Mec1,
in DNA damage checkpoint signaling and the oxidative stress
response, and discuss emerging ideas regarding the possible
mechanisms underlying the elaborate crosstalk between those
pathways. This review may provide new insights into the integrated
cellular strategies responsible for maintaining genome
stability in eukaryotes with a focus on the yeast model
organism.
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Woo-Hyun Chung
Journal of Microbiology.2023; 61(12): 1013. CrossRef - Metabolic Stress and Mitochondrial Dysfunction in Ataxia-Telangiectasia
Goutham Narayanan Subramanian, Abrey Jie Yeo, Magtouf Hnaidi Gatei, David John Coman, Martin Francis Lavin
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- Synthetic lethal interaction between oxidative stress response and DNA damage repair in the budding yeast and its application to targeted anticancer therapy
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Ji Eun Choi , Woo-Hyun Chung
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J. Microbiol. 2019;57(1):9-17. Published online December 29, 2018
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DOI: https://doi.org/10.1007/s12275-019-8475-2
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561
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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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Ji Eun Choi, Woo-Hyun Chung
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- To Peep into Pif1 Helicase: Multifaceted All the Way from Genome Stability to Repair-Associated DNA Synthesis
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Woo-Hyun Chung
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J. Microbiol. 2014;52(2):89-98. Published online February 1, 2014
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DOI: https://doi.org/10.1007/s12275-014-3524-3
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566
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Abstract
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Pif1 DNA helicase is the prototypical member of a 5' to 3' helicase superfamily conserved from bacteria to humans. In Saccharomyces cerevisiae, Pif1 and its homologue Rrm3, localize in both mitochondria and nucleus playing multiple roles in the maintenance of genomic homeostasis. They display relatively weak processivities in vitro, but have largely non-overlapping functions on common genomic loci such as mitochondrial DNA, telomeric ends, and many replication forks especially at hard-to-replicate regions including ribosomal DNA and G-quadruplex structures. Recently, emerging evidence shows that Pif1, but not Rrm3, has a significant new role in repair-associated DNA synthesis with Polδ during homologous recombination stimulating D-loop migration for conservative DNA replication. Comparative genetic and biochemical studies on the structure and function of Pif1 family helicases across different biological systems are further needed to elucidate both diversity and specificity of their mechanisms of action that contribute to genome stability.
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Citations
Citations to this article as recorded by - Signification and Application of Mutator and Antimutator Phenotype-Induced Genetic Variations in Evolutionary Adaptation and Cancer Therapeutics
Woo-Hyun Chung
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