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Identification of metabolic changes leading to cancer susceptibility in Fanconi anemia cells

E. Abad, S. Samino, RL. Grodzicki, G. Pagano, M. Trifuoggi, D. Graifer, D. Potesil, Z. Zdrahal, O. Yanes, A. Lyakhovich

. 2021 ; 503 (-) : 185-196. [pub] 20201211

Language English Country Ireland

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21025854

Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.

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$a Abad, Etna $u Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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$a Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.
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$a Samino, Sara $u Biosfer Teslab SL, Reus, Tarragona, Spain
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$a Grodzicki, Robert L $u Yale School of Medicine, Yale University, New Haven, CT, USA
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$a Pagano, Giovanni $u Department of Chemical Sciences, Federico II Naples University, I-80126 Naples, Italy
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$a Trifuoggi, Marco $u Department of Chemical Sciences, Federico II Naples University, I-80126 Naples, Italy
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$a Graifer, Dmitry $u Novosibirsk State University, Russian Federation
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$a Potesil, David $u CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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$a Zdrahal, Zbynek $u CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
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$a Yanes, Oscar $u Universitat Rovira i Virgili, Department of Electronic Engineering, IISPV, Tarragona 43007, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain
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$a Lyakhovich, Alex $u Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, 630117, Russia; Vall D'Hebron Institut de Recerca, 08035, Barcelona, Spain. Electronic address: alex.lyakhovich@mail.muni.cz
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