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Genomic integrity and mitochondrial metabolism defects in Warsaw syndrome cells: a comparison with Fanconi anemia
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-01-11 , DOI: 10.1002/jcp.30265 Roberta Bottega 1 , Silvia Ravera 2 , Luisa M R Napolitano 3 , Viviana Chiappetta 4 , Nicoletta Zini 5, 6 , Barbara Crescenzi 7 , Silvia Arniani 7 , Michela Faleschini 1 , Giuseppe Cortone 3, 8 , Flavio Faletra 1 , Barbara Medagli 3, 9 , Fabio Sirchia 1 , Martina Moretti 7 , Job de Lange 10 , Enrico Cappelli 11 , Cristina Mecucci 7 , Silvia Onesti 3 , Francesca M Pisani 4 , Anna Savoia 1, 12
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-01-11 , DOI: 10.1002/jcp.30265 Roberta Bottega 1 , Silvia Ravera 2 , Luisa M R Napolitano 3 , Viviana Chiappetta 4 , Nicoletta Zini 5, 6 , Barbara Crescenzi 7 , Silvia Arniani 7 , Michela Faleschini 1 , Giuseppe Cortone 3, 8 , Flavio Faletra 1 , Barbara Medagli 3, 9 , Fabio Sirchia 1 , Martina Moretti 7 , Job de Lange 10 , Enrico Cappelli 11 , Cristina Mecucci 7 , Silvia Onesti 3 , Francesca M Pisani 4 , Anna Savoia 1, 12
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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.
中文翻译：
华沙综合征细胞的基因组完整性和线粒体代谢缺陷：与范可尼贫血的比较
华沙断裂综合征 (WABS)，是由DDX11 的双等位基因突变引起的，一种编码 DNA 解旋酶的基因。我们最近报道了两个受影响的姐妹，复合杂合的错义 (p.Leu836Pro) 和移码 (p.Lys303Glufs*22) 变体。通过研究致病机制，我们证明 DDX11 p.Leu836Pro 突变体无法解开分叉的 DNA 底物，同时保留 DNA 结合活性。我们观察到患者来源细胞在 G2/M 期的积累和丝裂霉素 C 治疗后染色体断裂的增加。该表型与范可尼贫血细胞的特征部分重叠，这不仅显示出基因组不稳定性，而且显示出有缺陷的线粒体。这促使我们检查 WABS 细胞中的线粒体功能，并揭示了有氧代谢的改变。
更新日期：2021-01-11
中文翻译：
华沙综合征细胞的基因组完整性和线粒体代谢缺陷：与范可尼贫血的比较
华沙断裂综合征 (WABS)，是由DDX11 的双等位基因突变引起的，一种编码 DNA 解旋酶的基因。我们最近报道了两个受影响的姐妹，复合杂合的错义 (p.Leu836Pro) 和移码 (p.Lys303Glufs*22) 变体。通过研究致病机制，我们证明 DDX11 p.Leu836Pro 突变体无法解开分叉的 DNA 底物，同时保留 DNA 结合活性。我们观察到患者来源细胞在 G2/M 期的积累和丝裂霉素 C 治疗后染色体断裂的增加。该表型与范可尼贫血细胞的特征部分重叠，这不仅显示出基因组不稳定性，而且显示出有缺陷的线粒体。这促使我们检查 WABS 细胞中的线粒体功能，并揭示了有氧代谢的改变。
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