Defining Activities of KDMS Essential to Development and Viability

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ABSTRACT The Lysine demethylase 5 (KDM5) family of transcriptional regulators are important for normal development, and their dysregulation is a key driver of intellectual disability and several forms of cancer. Most work to-date has focused on the histone demethylase activity of KDM5 proteins, which targets the active chromatin mark H3K4me3. However, KDM5 proteins can also regulate transcription through non-enzymatic mechanisms. While KDM5 is essential for development, its demethylase activity is not required, as is demonstrated by the viability of demethylase-dead adult flies. In this work, we will examine essential functions of KDM5 via a novel truncation allele, kdm5Q19, which does not alter demethylase activity. kdm5Q19 inserts a stop codon in a previously unrecognized, evolutionarily conserved, motif within an intrinsically disordered region of KDM5 at the C-terminus. kdm5Q19 animals do not survive to adulthood, which is distinct from null, demethylase dead, and other mutants generated in our lab, suggesting that the motif disrupted by the truncation has an essential as-yet-unknown role in normal KDM5 function. To further dissect the molecular activities of this region of KDM5, we generate additional alleles of kdm5 to refine the critical region(s) of the protein and assess viability and changes to transcription. In this work, we will (1) define essential regions within KDM5 required for viability, and to characterize their roles in development (2) define the essential molecular functions imparted by the C-terminus of KDM5. Together, these studies will refine the critical region(s) of the C-terminus of KDM5, and define the normal role of these regions in regulating transcription.