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  1. Article ; Online: Genetically induced redox stress occurs in a yeast model for Roberts syndrome.

    Mfarej, Michael G / Skibbens, Robert V

    G3 (Bethesda, Md.)

    2021  Volume 12, Issue 2

    Abstract: Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N- ... ...

    Abstract Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for RBS and tumors that bear ESCO2 mutations.
    MeSH term(s) Acetyltransferases/genetics ; Acetyltransferases/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Chromatids ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Craniofacial Abnormalities ; Ectromelia/genetics ; Ectromelia/metabolism ; Ectromelia/pathology ; Humans ; Hypertelorism/genetics ; Hypertelorism/metabolism ; Hypertelorism/pathology ; Nuclear Proteins/genetics ; Oxidation-Reduction ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances Cell Cycle Proteins ; Chromosomal Proteins, Non-Histone ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; Acetyltransferases (EC 2.3.1.-) ; ECO1 protein, S cerevisiae (EC 2.3.1.-) ; ESCO2 protein, human (EC 2.3.1.-)
    Language English
    Publishing date 2021-12-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1093/g3journal/jkab426
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: DNA damage induces Yap5-dependent transcription of ECO1/CTF7 in Saccharomyces cerevisiae.

    Mfarej, Michael G / Skibbens, Robert V

    PloS one

    2020  Volume 15, Issue 12, Page(s) e0242968

    Abstract: Yeast Eco1 (ESCO2 in humans) acetyltransferase converts chromatin-bound cohesins to a DNA tethering state, thereby establishing sister chromatid cohesion. Eco1 establishes cohesion during DNA replication, after which Eco1 is targeted for degradation by ... ...

    Abstract Yeast Eco1 (ESCO2 in humans) acetyltransferase converts chromatin-bound cohesins to a DNA tethering state, thereby establishing sister chromatid cohesion. Eco1 establishes cohesion during DNA replication, after which Eco1 is targeted for degradation by SCF E3 ubiquitin ligase. SCF E3 ligase, and sequential phosphorylations that promote Eco1 ubiquitination and degradation, remain active throughout the M phase. In this way, Eco1 protein levels are high during S phase, but remain low throughout the remaining cell cycle. In response to DNA damage during M phase, however, Eco1 activity increases-providing for a new wave of cohesion establishment (termed Damage-Induced Cohesion, or DIC) which is critical for efficient DNA repair. To date, little evidence exists as to the mechanism through which Eco1 activity increases during M phase in response to DNA damage. Possibilities include that either the kinases or E3 ligase, that target Eco1 for degradation, are inhibited in response to DNA damage. Our results reveal instead that the degradation machinery remains fully active during M phase, despite the presence of DNA damage. In testing alternate models through which Eco1 activity increases in response to DNA damage, the results reveal that DNA damage induces new transcription of ECO1 and at a rate that exceeds the rate of Eco1 turnover, providing for rapid accumulation of Eco1 protein. We further show that DNA damage induction of ECO1 transcription is in part regulated by Yap5-a stress-induced transcription factor. Given the role for mutated ESCO2 (homolog of ECO1) in human birth defects, this study highlights the complex nature through which mutation of ESCO2, and defects in ESCO2 regulation, may promote developmental abnormalities and contribute to various diseases including cancer.
    MeSH term(s) Acetyltransferases/genetics ; Basic-Leucine Zipper Transcription Factors/metabolism ; DNA Damage ; Nuclear Proteins/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Transcription, Genetic
    Chemical Substances Basic-Leucine Zipper Transcription Factors ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; Yap5 protein, S cerevisiae ; Acetyltransferases (EC 2.3.1.-) ; ECO1 protein, S cerevisiae (EC 2.3.1.-)
    Language English
    Publishing date 2020-12-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0242968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: An ever-changing landscape in Roberts syndrome biology: Implications for macromolecular damage.

    Mfarej, Michael G / Skibbens, Robert V

    PLoS genetics

    2020  Volume 16, Issue 12, Page(s) e1009219

    Abstract: Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal ... ...

    Abstract Roberts syndrome (RBS) is a rare developmental disorder that can include craniofacial abnormalities, limb malformations, missing digits, intellectual disabilities, stillbirth, and early mortality. The genetic basis for RBS is linked to autosomal recessive loss-of-function mutation of the establishment of cohesion (ESCO) 2 acetyltransferase. ESCO2 is an essential gene that targets the DNA-binding cohesin complex. ESCO2 acetylates alternate subunits of cohesin to orchestrate vital cellular processes that include sister chromatid cohesion, chromosome condensation, transcription, and DNA repair. Although significant advances were made over the last 20 years in our understanding of ESCO2 and cohesin biology, the molecular etiology of RBS remains ambiguous. In this review, we highlight current models of RBS and reflect on data that suggests a novel role for macromolecular damage in the molecular etiology of RBS.
    MeSH term(s) Acetyltransferases/genetics ; Acetyltransferases/metabolism ; Animals ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Craniofacial Abnormalities/genetics ; Craniofacial Abnormalities/metabolism ; DNA Damage ; Ectromelia/genetics ; Ectromelia/metabolism ; Genomic Instability ; Humans ; Hypertelorism/genetics ; Hypertelorism/metabolism
    Chemical Substances Chromosomal Proteins, Non-Histone ; Acetyltransferases (EC 2.3.1.-) ; ESCO2 protein, human (EC 2.3.1.-)
    Language English
    Publishing date 2020-12-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1009219
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cohesin: an emerging master regulator at the heart of cardiac development.

    Mfarej, Michael G / Hyland, Caitlin A / Sanchez, Annie C / Falk, Matthias M / Iovine, M Kathryn / Skibbens, Robert V

    Molecular biology of the cell

    2023  Volume 34, Issue 5, Page(s) rs2

    Abstract: Cohesins are ATPase complexes that play central roles in cellular processes such as chromosome division, DNA repair, and gene expression. Cohesinopathies arise from mutations in cohesin proteins or cohesin complex regulators and encompass a family of ... ...

    Abstract Cohesins are ATPase complexes that play central roles in cellular processes such as chromosome division, DNA repair, and gene expression. Cohesinopathies arise from mutations in cohesin proteins or cohesin complex regulators and encompass a family of related developmental disorders that present with a range of severe birth defects, affect many different physiological systems, and often lead to embryonic fatality. Treatments for cohesinopathies are limited, in large part due to the lack of understanding of cohesin biology. Thus, characterizing the signaling networks that lie upstream and downstream of cohesin-dependent pathways remains clinically relevant. Here, we highlight alterations in cohesins and cohesin regulators that result in cohesinopathies, with a focus on cardiac defects. In addition, we suggest a novel and more unifying view regarding the mechanisms through which cohesinopathy-based heart defects may arise.
    MeSH term(s) Chromosomal Proteins, Non-Histone/metabolism ; Cell Cycle Proteins/metabolism ; Mutation ; Heart ; Cohesins
    Chemical Substances Chromosomal Proteins, Non-Histone ; Cell Cycle Proteins
    Language English
    Publishing date 2023-03-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E22-12-0557
    Database MEDical Literature Analysis and Retrieval System OnLINE

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