SPAIN – Researchers at the Centre for Genomic Regulation (CRG) in Barcelona, led by Miguel Beato, in collaboration with the University Pompeu Fabra, the Institute of Biomedical Research of Barcelona and the Rovira i Virgili University of Tarragona, have identified a new way of generating energy within the cell nucleus for chromatin remodeling and reprogramming of gene expression.

They also have discovered the function of enzymes involved in every step of this process and how they are activated in response to stress signals. Their findings, detailed in an article published in the journal Science, help in understanding the underlying mechanisms of chromatin remodeling, its relationship to DNA damage and cancer.

All our cells require small molecule called ATP (adenosine triphosphate), generated in the mitochondria to provide the necessary dynamic energy for cellular metabolism and growth. Particularly in cancer cells degree, ATP can also be generated in the cytoplasm from the energy obtained during the degradation of glucose.

These sources of ATP are sufficient to meet the energy needs of cells under normal conditions. However, in response to external signals that induce stress or extensive DNA damage, cells need to globally reprogram their gene expression pattern, a process that requires extensive chromatin remodeling to access regulatory information encoded in DNA.

The DNA in the cell nucleus is packaged into chromatin in a way that prevents access to the genetic information. The global reprogramming of gene expression to cope with stressful situations and high levels of DNA damage requires loosening the interaction of DNA with chromatin proteins. Modifying proteins consumes large amounts of energy chromatin and to meet these special needs, the cells require an extra amount of energy for a new pathway is activated in order to get more ATP available.

An enzyme, possible as cancer biomarker

Beato explained that exceptional situations require extraordinary measures. When the cells need to address a global reprogramming of gene expression require a lot of energy in the nucleus. In these situations, cells block their mitochondrial and cytosolic ATP to focus on the main task at the core production.

The scientists found that poly-ADP-ribose (PAR), one of the major players in stripping chromatin and repair of DNA damage is the basis of nuclear ATP synthesis. Its building blocks ADP-ribose are used by the nuclear enzyme NUDIX5 to generate ATP. Blocking the activity of NUDIX5 excludes chromatin remodeling, reprogramming of gene expression and cellular adaptation to stress or DNA damage.

Roni Wright, first author and postdoctoral researcher in CGR, concluded that their results point to NUDIX5 as a key player in the synthesis of ATP for nuclear chromatin remodeling. As NUDIX5 is overexpressed in several cancers, the main finding could contribute to targeted cancer medicine. NUDIX5 could be a biomarker for stratification of cancer and a potential new treatment for cancer in the future.