Affiliations: 1) Albert Einstein College of Medicine, Bronx, NY; 2) UMass Chan Medical School, Worcester, MA
Keywords: a. core promoters and general transcription factors; j. epigenetics
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 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.