ADP-Ribose derived nuclear of ATP generation in chromatin remodeling and gene regulation

ADP-Ribose derived nuclear of ATP generation in chromatin remodeling and gene regulation

Lioutas, Vicent, Wright

PARP1 mediated parylation is essential for hormonal gene regulation, but degradation of PAR by PARG is also important. Using ATP-reporters we found that in cells exposed to hormone the levels of ATP increase transiently in the cell nuclei, but not in mitochondria or in the cytoplasm. The nuclear ATP increase depends on PARP1 and PARG activity and cannot be blocked by blocking mitochondrial respiratory 10 min after hormone exposure. We identified NUDT5/NUDIX5 as a PAR-interacting enzyme that co-IP with PR and PARP1 and is needed for chromatin remodeling, gene regulation, and hormone-dependent cell proliferation. NUDIX5 forms a stable homodimer that hydrolyzes ADPR to AMP and R-5-P. In response to hormone NUDIX5 is rapidly dephophoryilated at T45 leading to destabilization of the homodimer that facilities the reaction of ADPR with pyrophosphate to generate ATP and R-5-P. We are exploring the structure of the enzyme chain involved in nuclear ATP synthesis, including NMNAT1, PARP1, PARG and NUDIX5 and their role in the DNA damage response and transcriptional activation. NUDIX5 is overexpressed in breast cancer samples and we want to develop small molecular weight inhibitors of ATP synthesis by NUDIX5 that could be of use in cancer therapy, alone or in combination with PARP inhibitors.