Nuclear localization of MTHFD2 is required for correct mitosis progression
Natalia Pardo‐Lorente, Anestis Gkanogiannis, Luca Cozzuto, Antoni Gañez Zapater, Lorena Espinar, Ritobrata Ghose, Jacqueline Severino, Laura García–López, Rabia Gül Aydin, Laura Martin, Maria Victoria Neguembor, Evangelia Darai, Maria Pia Cosma, Laura Batlle‐Morera, Julia Ponomarenko, Sara Sdelci
Abstract
Subcellular compartmentalization of metabolic enzymes establishes a unique metabolic environment that elicits specific cellular functions. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we show that the nuclear localization of the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) ensures mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces severe methylation defects and impedes correct mitosis completion. MTHFD2 deficient cells display chromosome congression and segregation defects and accumulate chromosomal aberrations. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, whereas restricting MTHFD2 to the nucleus is sufficient to ensure correct mitotic progression. Our discovery uncovers a nuclear role for MTHFD2, supporting the notion that translocation of metabolic enzymes to the nucleus is required to meet precise chromatin needs. The nuclear localization of metabolic enzymes is fascinating and in most cases remains a mystery. Here, Pardo Lorente and colleagues show that nuclear MTHFD2 is required for successful mitosis by controlling centromeric histone methylation.