Browsing by Author "Jirik, Frank R."

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    The Pace of Prostatic Intraepithelial Neoplasia Development Is Determined by the Timing of Pten Tumor Suppressor Gene Excision
    (Public Library of Science, 2009) Luchman, H. Artee; Benediktsson, Hallgrimur; Villemaire, Michelle L.; Peterson, Alan C.; Jirik, Frank R.
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    The Roles of ING5 in Regeneration and Maintaining Genomic Stability (in vivo model)
    (2023-08) Al Shueili, Buthaina; Raibowol, Karl T.; Jirik, Frank R.; Rancourt, Derrick E.
    In this thesis, we provide the first in vivo description of the functions of ING5, a member of the INhibitor of Growth (ING1-5) proteins that are epigenetic regulators. INGs target histone acetyltransferase (HAT) or histone deacetylase (HDAC) complexes to the H3K4Me3 mark of active transcription. ING5 targets MOZ/MORF and HBO1 HAT complexes to acetylate H3 and H4 core histones, respectively, affecting gene expression. Previous in vitro studies by us and others indicated that ING5 maintains stem cell character in normal and cancer stem cells. Moreover, ING5 has also been implicated in maintaining genomic stability by regulating post-translational modification of DNA repair proteins. Here we find that CRISPR/Cas9 ING5 knockout (KO) mice are sub-fertile but viable and show no decrease in lifespan despite signs of depleted stem cell pools in their brains, skin and peripheral nerves. Cardiac Fibroblasts established from knockout animals had accelerated growth rates, with higher heart fibrosis after an infarct injury. Evidence of chondrogenesis was also obtained in knockout hearts that had compromised heart function, indicating the significance of ING5 for heart integrity. Depletion of ING5 also affected DNA repair, as suggested by the accumulation of DNA damage and apoptosis in the testis, which affected animal fertility. Furthermore, middle-aged to old KO animals develop lymphomas at a rate approximately 6-fold higher than control mice. This may be due to loss of ING5 resulting in p53 instability, with several tissues showing very low or undetectable levels of p53 despite normal levels of p53 mRNA.