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    Conservation and Regulation of the Essential Epigenetic Regulator UHRF1 Across Vertebrata Orthologs

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    Name:
    Master's thesis_Abrar Aljahani_Spring 2020.pdf
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    16.47Mb
    Format:
    PDF
    Description:
    MS Thesis
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    Type
    Thesis
    Authors
    Aljahani, Abrar cc
    Advisors
    Fischle, Wolfgang cc
    Committee members
    Arold, Stefan T. cc
    Aranda, Manuel cc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2020-05
    Embargo End Date
    2020-05-10
    Permanent link to this record
    http://hdl.handle.net/10754/662803
    
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    Show full item record
    Access Restrictions
    At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis became available to the public after the expiration of the embargo on 2020-05-10.
    Abstract
    UHRF1 is a critical epigenetic regulator which serves as a molecular model for understanding the crosstalk between histone modification and DNA methylation. It is integrated in the process of DNA maintenance methylation through its histone ubiquitylation activity, ultimately functioning as a recruiter of DNA methyltransferase 1 (DNMT1). As the faithful propagation of DNA methylation patterns during cell division is a common molecular phenomenon among vertebrates, understanding the underlying conserved mechanism of UHRF1 for executing such a key process is important. Here, I present a broad-range evolutionary comparison of UHRF1 binding behavior and enzymatic activity of six species spanning across the vertebrata subphylum. According to their distinct binding modes to differentially methylated histone H3, a pattern is emerging which separates between mammalian and nonmammalian orthologs. H. sapiens, P. troglodytes and M. musculus UHRF1 orthologs utilize the functionality of both TTD and PHD domains to interact with histone H3 peptides, while G. gallus, X. laevis, and D. rerio employ either TTD or PHD. Further, UHRF1 allosteric regulation by 16:0 PI5P is a unique case to primate orthologs where H3K9me3 peptide binding is enhanced upon hUHRF1 and pUHRF1 interacting with 16:0 PI5P. This is due to their closed and autoinhibited conformation wherein TTD is blocked by the PBR region in linker 4. 16:0 PI5P outcompetes TTD for PBR binding resulting in a release of TTD blockage, hence, enhanced H3K9me3 binding. However, owing to the lack of phosphatidylinositol binding specificity and reduced sequence conservation of linker 4, the regulatory impact of 16:0 PI5P in avian and lower vertebrate orthologs could not be detected. Additionally, all UHRF1 orthologs exert their ubiquitylation enzymatic activity on histone H3 substrates, supporting the notion that the overall functionality of UHRF1 orthologs is conserved, despite their divergent molecular approaches. Taken together, my findings suggest that UHRF1 orthologs adopt distinct conformational states with a differential response to the allosteric regulators 16:0 PI5P and hemi-methylated DNA.
    Citation
    Aljahani, A. (2020). Conservation and Regulation of the Essential Epigenetic Regulator UHRF1 Across Vertebrata Orthologs. KAUST Research Repository. https://doi.org/10.25781/KAUST-5G95S
    DOI
    10.25781/KAUST-5G95S
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-5G95S
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Theses

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