Abstract

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists, results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.

Highlights

  • It is widely accepted that chromosome aberrations (CABs) can contribute to cancer development

  • We show that the active form of vitamin B6 (Pyridoxal 59phosphate, Pyridoxal 59-phosphate (PLP)) plays an important role in the maintenance of genome integrity

  • The mutagenic effects of sugars in the presence of PLP deficiency are evolutionarily conserved, as PLP depletion or inhibition in human cells results in CAB formation, which is potentiated by glucose or fructose

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Summary

Introduction

It is widely accepted that chromosome aberrations (CABs) can contribute to cancer development. Tumor development has been associated with chromothripsis, a phenomenon of massive DNA fragmentation followed by multiple chromosomal rearrangements involving between one and a dozen of chromosomes [4,5,6]. It is currently unclear whether cells with chromothripsis are generated by a single event or result from multiple successive events involving more than one cell cycle [7,8,9]. NHEJ joins broken chromosome ends directly and relies on the activities of the Mre11-Rad50-Nbs (MRN) complex, the Ku heterodimer, and the Ligase 4 complex. Mutations in ATM (Ataxia Telangiectasia Mutated), MRE11, NBS1 (Nijmegen Breakage Syndrome), BRCA1 (Breast Cancer 1), BRCA2 and Ligase 4 cause human syndromes characterized by both CABs and cancer predisposition, highlighting the connection between CABs and cancer [14,15]

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