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.
| Identifer | oai:union.ndltd.org:kaust.edu.sa/oai:repository.kaust.edu.sa:10754/662803 |
| Date | 05 1900 |
| Creators | Aljahani, Abrar |
| Contributors | Fischle, Wolfgang, Biological and Environmental Sciences and Engineering (BESE) Division, Arold, Stefan T., Aranda, Manuel |
| Source Sets | King Abdullah University of Science and Technology |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | 2020-05-10, 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. |
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