Characterization of the novel histone methyl lysine binding motif of the DEAD-box helicase DDX19A and analysis of its molecular and cellular function

• Applicant: Dr. Philipp Rathert
• Subject Area: Biochemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513657057

In a publication from our laboratory, we described a novel function ofthe DEAD-box helicase DDX19A that contributes to LSD1-mediated gene repression via removal of transcription-associated R-loops.Furthermore, specific binding of DDX19A to trimethylated lysine 27 ofhistone H3 (H3K27me3) and trimethylated lysine 20 of histone H4(H4K20me3) was observed (Pinter et al., 2021). The biologicalfunction of this interaction remains incompletely understood. However,the high affinity of DDX19A for histone modifications associated withgene repression suggests either a possible role in recruitment ofDDX19A to chromatin or a mechanism to stimulate its helicase activityto remove transcription-associated R-loops during the transition froman actively transcribed to a repressed gene. To date, DDX19A has notbeen reported to interact with modified histones, and it does notcontain any of the previously known histone reading domains. Theproject described aims to further investigate the mechanistic effects ofDDX19A binding to H3K27me3 and H4K20me3 to improve ourunderstanding of the core functions of DDX19A. Our results mayextend to additional DEAD/H-box helicases and may reveal possibleadditional unknown regulatory pathways of these helicases.Furthermore, these poorly studied binding motifs may ultimately leadto new approaches for therapeutic targeting of these proteins.

• DFG Programme: Research Grants