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Cells Tap Nuclear Energy to Drive Urgent DNA Repair

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The cell’s everyday energy needs are satisfied by adenosine triphosphate (ATP) molecules from mitochondria. But in extraordinary circumstances, alternative sources of ATP are available. For example, in fast-proliferating cancer cells, ATP can be generated in the cytoplasm. Because alternative ATP can be used to power cancer cells, it is in danger of getting a bad name. Alternative ATP, however, can serve useful purposes, too.

According to a new study from Spain’s Center for Genomic Regulation (CRG), distressed cells can generate nuclear ATP. Such cells, if challenged by extensive DNA damage or signals of external threats, can activate an alternative ATP-generating pathway that can support emergency repairs or regulatory responses that require extensive chromatin remodeling.

The new findings appeared June 3 in the journal Science, in an article entitled, “ADP-Ribose–Derived Nuclear ATP Synthesis by NUDIX5 Is Required for Chromatin Remodeling.” The article describes how the energy needed to remodel chromatin can be derived from a source in the cell nucleus, rather than by the diffusion of ATP from the mitochondria in the cytoplasm. In particular, the article clarifies how the ATP demands imposed by urgent chromatin remodeling can be satisfied.

“We 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 [adenosine diphosphate]-ribose) to ADP-ribose,” wrote the authors of the Science article. “In the presence of pyrophosphate, ADP-ribose is used by the pyrophosphatase NUDIX5 to generate nuclear ATP.”

The scientists at CRG, in collaboration with scientists from the University Pompeu Fabra, the Institute for Biomedical Research in Barcelona, and the University Rovira i Virgili in Tarragona, Spain, have described for the first time a new pathway that can generating energy within the cell nucleus and support the remodeling chromatin and the reprogramming of gene expression. These scientists have also identified the function of enzymes involved at every step of this process and how they are activated in response to stress signals.

“Exceptional situations call for extraordinary measures,” said Miguel Beato, group leader at CRG and principal investigator of this paper. “When cells need to cope with a global reprogramming of gene expression, they require a lot of energy in the nucleus. In these situations, the cells block their mitochondrial and cytosolic ATP production to be focused on the main task in the nucleus.”

Ordinarily, chromatin keeps DNA tightly packed, keeping genetic information tucked away, unavailable for replication and repair. Global reprogramming of gene expression to deal with stressful situations and high levels of DNA damage requires loosening the interaction of DNA with chromatin proteins. The modification of chromatin proteins consumes large amounts of energy.

Researchers found that poly(ADP-ribose) (PAR), one of the main actors in chromatin decompaction and DNA damage repair, is the cornerstone for the nuclear ATP synthesis. Its building blocks of ADP-ribose are used by the nuclear enzyme NUDIX5 to generate ATP. Blocking NUDIX5 activity precludes chromatin remodeling, reprogramming of gene expression, and the cell’s adaptation to stress or DNA damage.

“Our results point to NUDIX5 as a key player in nuclear ATP synthesis for chromatin remodeling. Since NUDIX5 is overexpressed in various types of cancer, this fundamental finding could contribute to targeted cancer medicine. NUDIX5 could be a biomarker for cancer stratification and a new potential target for future cancer treatment,” concluded Roni Wright, first author of the paper and CRG postdoctoral researcher.

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