ADP-ribose derived Nuclear ATP is Required for Chromatin Remodeling and Hormonal Gene Regulation

Highlights- Hormonal gene regulation requires synthesis of PAR and its degradation to ADP-ribose by PARG\n- ADP-ribose is converted to ATP in the cell nuclei by hormone-activated NUDIX5/NUDT5\n- Blocking nuclear ATP formation precludes hormone-induced chromatin remodeling, gene regulation and cell proliferation\n\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=165 HEIGHT=200 SRC=\"FIGDIR/small/006593v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (46K):\norg.highwire.dtl.DTLVardef@e2c9fborg.highwire.dtl.DTLVardef@13ab596org.highwire.dtl.DTLVardef@16799d7org.highwire.dtl.DTLVardef@a53086_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryKey nuclear processes in eukaryotes including DNA replication or repair and gene regulation require extensive chromatin remodeling catalyzed by energy consuming enzymes. How the energetic demands of such processes are ensured in response to rapid stimuli remains unclear. We have analyzed this question in the context of the massive gene regulation changes induced by progestins in breast cancer cells and found that ATP is generated in the cell nucleus via the hydrolysis of poly-ADP-ribose to ADP-ribose. Nuclear ATP synthesis requires the combined enzymatic activities of PARP1, PARG and NUDIX5/NUDT5. Although initiated via mitochondrial derived ATP, the nuclear source of ATP is essential for hormone induced chromatin remodeling, gene regulation and cell proliferation and may also participate in DNA repair. This novel pathway reveals exciting avenues of research for drug development.