JUN 11, 2016 6:40 AM PDT

When Cells Need Extra Energy, There's a Plan B for Generating It

WRITTEN BY: Carmen Leitch
ATP is a critical molecule. Required by all cells and made by the mitochondria, it’s the energy source for processes such as growth, metabolism and dynamics. In some cases, ATP can be created in the cytoplasm when glucose is degraded. All of that ATP is enough to meet the needs of the cell under typical conditions.
 The level of organizational packing can have serious consequences on DNA-mediated processes like gene regulation. Euchromatin (loose or open chromatin) structure is permissible for transcription whereas heterochromatin (tight or closed chromatin) is more compact and inhibitory to factors that need to get access to the DNA template. By Sha, K. and Boyer, L. A., stemBook 2009
When the cell is under stress from its environment or when there is extensive damage to its DNA, cells have to totally rearrange their gene expression patterns. Normally, DNA is tightly packed, coiled around proteins as chromatin and arranged such that regulatory elements are not readily available. Chromatin has to be loosened and relaxed so gene expression can be reprogrammed, and the easing of the interaction between DNA and its associated proteins consumes so much energy, the cell uses a new pathway to generate the extra ATP required.

In new work published in Science, Miguel Beato led researchers at the Centre for Genomic Regulation (CRG) in collaboration with scientists at the University Pompeu Fabra’s Institute for Biomedical Research in Barcelona and the University Rovira i Virgili in Tarragona, Spain. They have described a brand new way of creating energy inside the nucleus of cells, specifically for rearranging chromatin and reprogramming gene expression. The way that stress signals activate the various enzymes required for this process was also described and characterized. 

Hopefully, these results will aid in understanding how chromatin is remodeled as well as its relationship with DNA damage and as such, with cancer.

"Exceptional situations call for extraordinary measures. 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," explains Miguel Beato, the principal investigator of this study. 
  Crystal structure of the NUDIX5 homodimer complex with ADPR and Mg2+ (PDB: 2DSC). Top: Two symmetrical contacts between T45D (blue) and K27 from the complementary chains indicated with arrows. Bottom: View of the active site of T45D with ADPR and Mg2+ (green sphere)
The researchers found that poly-ADP-ribose (PAR), one of the main players in the decompaction of chromatin and DNA damage repair, is the cornerstone for nuclear ATP synthesis. The nuclear enzyme NUDIX5 is able to generate ATP from the ADP-ribose that makes up the PAR. When NUDIX5 activity is blocked, chromatin remodeling does not occur, meaning reprogramming of gene expression is precluded. The cell is this unable to adaptat to stress or repair DNA damage.

Roni Wright, first author of the paper and a CRG postdoctoral researcher concludes, “Our results point to NUDIX5 as 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.”

Sources: Science, AAAS 
About the Author
  • Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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