KDM5 interacts with heat shock factor (Hsf) to regulate cellular response to oxidative stress. Xingyin Liu, Christina Greer, Juile Secombe. Genetics, Albert Einstein Med College, Bronx, NY.

   Drosophila KDM5 (also known as Lid) and its four mammalian homologs, KDM5A, KDM5B, KDM5C and KDM5D, are multi-domain transcriptional regulators. In humans, KDM5A or KDM5B overexpression causes breast, gastric and prostate cancers, and loss of KDM5C results in intellectual disability. However, a confounding factor to the analysis of the four mammalian KDM5 paralogs is their functional redundancy. In contrast, Drosophila has a single, essential KDM5 protein, providing an ideal system to answer fundamental questions regarding the mechanisms by which KDM5 regulates gene expression, and to cast light on how KDM5 function goes awry in human disease. While KDM5 proteins are most famous for their JmjC domain-encoded histone demethylase activity, we have shown that this activity is not required for viability. To investigate demethylase-independent functions of KDM5, we use microarrays to identify genes differentially expressed in response to KDM5 overexpression. Gene ontology analysis revealed a significant enrichment of genes involved in the response to oxidative stress. Consistent with this, we find that modulating KDM5 levels confers resistance or sensitivity to the oxidative stress agent paraquat when overexpressed or reduced, respectively. Because activation Hsp22 is essential for cells to survive conditions of oxidative stress, we are focusing on the mechanism by which KDM5 transcriptionally regulates this gene. Based on our preliminary data, we propose that KDM5 interacts with the renown stress response factor, Heat shock transcription factor (Hsf) to directly activate Hsp22 and that this occurs via KDM5-mediated inhibition of the histone deacetylase HDAC1. Our results provide a mechanistic basis for KDM5s role in the regulation of oxidative stress. Importantly, because increased levels of reactive oxygen species (ROS) is a feature of many neurological disorders, our data suggest that oxidative stress-induced cellular damage may be a major contributor to intellectual disability caused by mutations in human KDM5C.