Genomic integrity and mitochondrial metabolism defects in Warsaw syndrome cells: a comparison with Fanconi anemia. Issue 8 (11th January 2021)

• Record Type: Journal Article
• Authors: Bottega, Roberta; Ravera, Silvia; Napolitano, Luisa M. R.; Chiappetta, Viviana; Zini, Nicoletta; Crescenzi, Barbara; Arniani, Silvia; Faleschini, Michela; Cortone, Giuseppe; Faletra, Flavio; Medagli, Barbara; Sirchia, Fabio; Moretti, Martina; de Lange, Job; Cappelli, Enrico; Mecucci, Cristina; Onesti, Silvia; Pisani, Francesca M.; Savoia, Anna
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 8(2021)
• Page Start: 5664
• Page End: 5675
• Publication Date: 2021-01-11
• Subjects: Fanconi anemia -- genomic integrity -- mitochondrial defects -- oxidative stress -- OXOPHOS -- Warsaw syndrome; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30265
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Warsaw breakage syndrome (WABS), is caused by biallelic mutations of DDX11, a gene coding a DNA helicase. We have recently reported two affected sisters, compound heterozygous for a missense (p.Leu836Pro) and a frameshift (p.Lys303Glufs*22) variant. By investigating the pathogenic mechanism, we demonstrate the inability of the DDX11 p.Leu836Pro mutant to unwind forked DNA substrates, while retaining DNA binding activity. We observed the accumulation of patient‐derived cells at the G2/M phase and increased chromosomal fragmentation after mitomycin C treatment. The phenotype partially overlaps with features of the Fanconi anemia cells, which shows not only genomic instability but also defective mitochondria. This prompted us to examine mitochondrial functionality in WABS cells and revealed an altered aerobic metabolism. This opens the door to the further elucidation of the molecular and cellular basis of an impaired mitochondrial phenotype and sheds light on this fundamental process in cell physiology and the pathogenesis of these diseases. Abstract : This study reports for the first time that Warsaw breakage syndrome (WABS), an ultra‐rare genetic disease is characterized by an altered aerobic metabolism of mitochondria. This feature is in common with Fanconi anemia (FA), a cancer‐prone genetic disease caused by genomic instability due to a defective DNA repair machinery. The association of DDX11 mutations, as well as FA ones, with defective mitochondrial activity, is intriguing not only to shed light on this fundamental process in cell physiology but also to fully understand the pathogenesis of these diseases.