Researchers at the Centre for Genomic Regulation (CRG) reveal that metabolic enzymes known for their roles in energy production and nucleotide synthesis are taking on unexpected “second jobs” within the nucleus, orchestrating critical functions like cell division and DNA repair. The discovery, reported across two separate research papers out today in Nature Communications, not only challenges longstanding biological paradigms in cellular biology but also opens new avenues for cancer therapies, particularly against aggressive tumours like triple-negative breast cancer (TNBC). For decades, biology textbooks have neatly compartmentalised cellular functions. Mitochondria are the powerhouses of the cell, the cytoplasm is a bustling factory floor for protein synthesis, and the nucleus a custodian of genetic information. However, the team at the CRG have discovered that the boundaries between these cellular compartments are less defined than previously thought.
In one of the studies, researcher Dr. Natalia Pardo Lorente focused on the metabolic enzyme MTHFD2. Traditionally, MTHFD2 is found in the mitochondria, where it plays a key role in synthesising nucleotides using folate cofactors as a bridge. CRG scientists now reveals that MTHFD2 also moonlights within the nucleus, where it plays a pivotal role in ensuring proper cell division. The study is the first to demonstrate that the nucleus relies on metabolic pathways to maintain the integrity and stability of the human genome. In the second study, researchers turned their attention to triple-negative breast cancer, the most aggressive type of breast cancer there is. The disease is responsible for around one in eight breast cancer diagnoses and amounts to roughly 200,000 new cases each year worldwide. Usually, excessive DNA damage triggers cell death. However, TNBC has a propensity to accumulate DNA damage without consequence, making it resilient to conventional treatments.
The study helps partly explain why: the metabolic enzyme IMPDH2 relocates to the nucleus of TNBC cells to assist in DNA repair processes. IMPDH2 acts like a mechanic in the cell’s nucleus, controlling the DNA damage response that would otherwise kill the cancer cell. This gene encodes the rate-limiting enzyme in the de novo guanine nucleotide biosynthesis. It is thus involved in maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. IMPDH2 catalyzes the NAD-dependent oxidation of inosine-5′-monophosphate (IMP) into xanthine-5′-monophosphate (XMP) and then into guanosine-5′-monophosphate (GMP). Overexpressing IMPDH2 in cancer cells could promote G1/S phase cell cycle transition through activation of PI3K/AKT/FoxO1 and PI3K/AKT/mTOR pathways and facilitate cell invasion and migration. Scientists still do not know if this is related to nucleotide production or other activities of this enzyme.
However, there is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesisBy experimentally manipulating IMPDH2 levels, the team found they could tip the balance. Increasing IMPDH2 within the nucleus overwhelmed the cancer cells’ repair machinery, causing cells to self-destruct. Their approach effectively forces TNBC cells to succumb to the very DNA damage they are typically resilient to. The study can also lead to new ways of monitoring cancer. The research on IMPDH2 also studied its interaction with the enzyme PARP1 (poli-ADP-ribose polymerase), a protein already targeted by existing cancer drugs. PARP1 is similar to p53 tumor suppressor in being a genome guardian. This enzyme becomes activated by DNA strand breaks and modifies tens of proteins that cowork to repair the damage. Then, activation of p53 can inhibit cellular IMPDH2 activity and reduce cellular GTP level thereby repressing cancer cell growth, as shown by other investigations.
Both studies contribute to an emerging field of therapies targeting cancer by exploiting its metabolic vulnerabilities. With these informations, scientists deem that IMPDH2 could serve as a biomarker to predict which tumours will respond to PARP1 inhibitors. In addition it could represent an innovational doouble whammy to hit cancer cells and force them to die: by disrupting their energy production while simultaneously impairing their ability to repair DNA and divide properly.
- Edited to Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Espinar L et al. Nat Commun. 2024 Nov 12; 15(1):9515.
Li L et al. J Cancer Res Clin Oncol. 2024 Aug; 150(8):377.
Huang Y, Chan S et al. J Transl Med. 2024; 22(1):133.