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

Key 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. Overall design: 1) Hormonal gene regulation requires synthesis of PAR and its degradation to ADPribose by PARG. 2) ADP-ribose is converted to ATP in the cell nuclei by hormone-activated NUDIX5/NUDT5. 3) Blocking nuclear ATP formation precludes hormone-induced chromatin remodeling, gene regulation and cell proliferation.