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Browsing Biology by Subject "14-3-3"
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Item Open Access Identification of Regions Required for CDCA7 Interaction with DNA Damage Repair Machinery(2023-12-08) Jaff, Shaina Rachel; Scheid, MichaelCDCA7 (Cell Division Cycle Associated Protein 7) is a transcription factor protein that binds to DNA and histone modifying enzymes supporting DNA methylation and contributes to repair of double stranded breaks in DNA. Mutations of the cdca7 gene cause ICF (Immunodeficiency, centromeric instability, and facial abnormalities) syndrome. CDCA7 has been shown to bind with HELLS (Helicase, lymphoid specific) as a bipartite nucleosome remodeller to allow for de novo methylation by DNMT3b (DNA methyl transferase 3b). Additionally, CDCA7 associates with Ku70 and Ku80, proteins essential for DNA damage repair via the Non-Homologous End Joining (NHEJ) pathway, and -H2AX, whose accumulation is facilitated by Ku proteins and is a biomarker of DNA damage. I show here that CDCA7 requires a putative leucine zipper for association with HELLS, while the binding of 14-3-3 at a phosphorylated residue in CDCA7 regulates Ku70/80 and -H2AX association. This study further elucidates the mechanism of how CDCA7 plays a crucial role in maintaining genomic stability by participating in various DNA repair processes and DNA methylation.Item Open Access Role of MEKK2 Phosphorylation at Threonine 263 on SMYD3-Mediated Methylation of Lysine 260(2024-07-18) Corridore, Rachel Nicole; Scheid, MichaelMEKK2 is a protein serine/threonine-kinase involved in the activation of many MAP-kinase signalling pathways. In a previous study, SMYD3-mediated methylation at K260 of MEKK2 was demonstrated to promote aberrant input downstream of oncogenic Ras-signaling, promoting Ras-driven PDAC and LAC progression. Our lab has previously characterized the role of MEKK2 phosphorylation at T283 and has recently discovered a novel second phosphorylation site at T263. We show that together, these sites form the bipartite binding group for 14-3-3 adapter proteins. This study focuses on characterizing T263 and T283 as regulatory phosphosites in K260 methylation and implicates 14-3-3 as a promoting factor in facilitating SMYD3-mediated methylation at K260. Our findings provide a potential mechanism of MEKK2 oncogenic function, whereby 14-3-3 preserves phosphorylation at T263 and T283, together promoting K260 methylation and MEKK2 activation. Our study characterizes T263 and T283 of MEKK2 and 14-3-3 phosphoadapter proteins as potential therapeutic targets in PDAC and LAC.