HISTONE-TAIL RECOGNITION BY THE PHD1 FINGER OF H3K4 DEMETHYLASE KDM5B IS REGULATED BY AN H3-TAIL MIMIC PEPTIDE BUT UNAFFECTED BY SEROTONYLATION OF H3Q5

Abstract

Methylation of lysine-4 of histone H3 (H3K4) plays a crucial role in the regulation of chromatin structure and gene transcription. KDM5B is an enzyme responsible for demethylating this residue, and its dysregulation has been implicated in the proliferation and invasive migration of cancer cells. This enzyme contains a PHD1 finger domain, which has previously been shown to associate with the unmodified N-terminal tail of histone H3. An unpublished finding from our lab suggests that a peptide sequence in KDM5B may mimic this histone tail. Thus, PHD1 may interact with this histone-tail mimic peptide to induce a conformation in KDM5B that intrasterically inhibits the enzyme. However, it is not known whether this interaction take place. Additionally, a serotonylation of glutamine-5 of histone H3 (H3Q5) has recently been identified as a novel histone modification. Given the sensitivity of PHD1 to nearby modifications, serotonylation of this residue may inhibit demethylation, resulting in the inhibition of KDM5B. Here, we use HSQC NMR titration to identify whether PHD1 interacts with the presumptive histone-tail mimic peptide and whether serotonylation of H3Q5 modulates the recognition of H3K4 by PHD1. Successful completion of this study will provide insight into the regulation of KDM5B, potentially contributing to therapeutic strategies for the treatment of cancers and other gene regulatory disorders.