Bone marrow cell transcripts from Fanconi anaemia patients reveal in vivo alterations in mitochondrial, redox and DNA repair pathways

Abstract

Fanconi anaemia (FA) is a genetic cancer predisposition disorder associated with cytogenetic instability, bone marrow failure and a pleiotropic cellular phenotype, including low thresholds of responses to oxidative stress, cross-linking agents and selected cytokines. This study was aimed at defining the scope of abnormalities in gene expression using the publicly available FA Transcriptome Consortium (FTC) database (Gene Expression Omnibus, 2009 and publicly available as GSE16334). We evaluated the data set that included transcriptomal analyses on RNA obtained from low-density bone marrow cells (BMC) from 20 patients with FA and 11 healthy volunteers, by seeking to identify changes in expression of over 22,000 genes, including a set of genes involved in: (i) bioenergetic pathways; (ii) antioxidant activities; (iii) response to stress and metal-chelating proteins; (iv) inflammation-related cytokines and (v) DNA repair. Ontological analysis of genes expressed at magnitudes of 1.5-fold or greater demonstrated significant suppression of genes in the categories of (i) energy metabolism; (ii) antioxidant activities; and (iii) stress and chelating proteins. Enhanced expression was found for 16 of 26 genes encoding inflammatory cytokines. A set of 20 of 21 transcripts for DNA repair activities were down-regulated; four of these transcripts related to type II topoisomerase. The data provide evidence for alterations in gene regulation of bioenergetic activities, redox-related activities, stress and metal-chelating proteins, and of some selected DNA repair activities in patients with FA.

Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

“…Three independent studies of MDF in FA cell lines of different genetic subtypes provided evidence for abnormal ultrastructure and function of mitochondria in FA cells [57–59]. Our recent report on bone marrow cell transcripts from FA patients revealed downregulation of genes involved in mitochondrial functions, antioxidant activities, heat shock proteins, and chelating proteins [60]. Thus, the role in the FA phenotype of OS/MDF may be considered well established and awaits consequent interventions in clinical management, in view of preventing or delaying disease progression.…”

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

“…A number of additional DNA repair factors associate with FA proteins [40]. Recent study of transcripts from bone marrow cells revealed that FA patients have deficiencies in mitochondrial, redox and DNA repair pathways [41,42]. Another DNA-repair deficient disease is Ataxia Telangiectasia (AT) that is caused by mutations on the ATM gene [43].…”

Fancd2 in vivo interaction network reveals a non-canonical role in mitochondrial function

“…Since FA proteins have been shown to regulate oxidative stress and mitochondrion respiration complex enzymes91213161718, and since mitochondrial Fancd2-interactors show the highest enrichment score in our proteomic analysis (Fig. 2 above), we decided to study the link between FA and the mitochondrion further.…”

“…For example, several studies show that FA cells exhibit abnormalities in mitochondrial metabolism, Ca 2 + homeostasis, and gene expression91011. Additional studies revealed mitochondrion defects in FA patients and mice12131415.…”