A genetic screen in yeast has found a surprising link between vitamin B6 deficiency and increased genome instability, a hallmark of cancerous cells. This study gives new insights into the causes of genetic aberrations, and provides a possible mechanistic explanation for epidemiological evidence that suggests a link between micronutrient deficiencies and cancer risk.

When faithful DNA replication is disrupted, genetic lesions are created. If the DNA-repair pathways that correct these lesions are faulty, illegitimate repair can result in gross chromosomal rearrangements (GCRs) such as translocations, amplifications, inversions and deletions. In particular, break-induced replication (BIR), a type of homologous recombination repair, is thought to be a major mechanism by which GCRs occur.

Kanellis and colleagues engineered a Saccharomyces cerevisiae strain that includes a GCR reporter located at a chromosomal position at which rearrangements take place by BIR. In a genome-wide screen, the authors picked out BUD16 as a potent suppressor of GCR, and alignment studies revealed that this gene encodes a putative pyridoxal kinase (Pdxk), an enzyme that is crucial for the metabolism of vitamin B6 to produce pyridoxal 5′ phosphate (PLP), the biologically active form. Strikingly, bud16Δmutant cells have a 124-fold increased GCR rate compared with wild-type cells, coinciding with a reduction in PLP levels to 1.8%.

Rad52 is essential for homologous recombination and hence DNA repair. bud16Δ rad52Δdouble mutants showed synthetic sickness and poor viability, suggesting that bud16Δcells have high levels of DNA disruption during replication, and rely on Rad52-mediated repair for survival. Furthermore, fluorescence microscopy showed that, after budding, Rad52 foci (or 'repair centres') were present in 57–75% of bud16Δcells, compared with 2–21% in wild-type cells.

But do these symptoms of replication stress necessarily result from PLP depletion? By interfering with components of the PLP pathway, the authors generated a similar GCR phenotype to that of bud16Δcells. Similar results were seen in mammalian cells: addition of a vitamin B6 analogue that inhibits PDXK in human cells (thereby reducing PLP levels) resulted in the induction of DNA lesions and activation of the DNA-damage response.

PLP is an essential cofactor in dTMP synthesis pathways; might this be the mechanism by which it prevents DNA lesions? bud16Δcells have significantly higher uracil levels in their DNA compared with wild-type cells. It seems likely that the bud16Δ mutation, by disrupting Pdxk's role in nucleotide synthesis, causes an increase in dUMP pools, promoting incorporation of dUTP into DNA during replication. Uracil-excision processes might then promote the occurrence of lesions, leading to chromosomal instability.

Interestingly, the authors go on to propose that the cellular response to low PLP could actually represent a defense mechanism against cancer — depletion of metabolites resulting from overproliferation of cancerous cells might be sensed by the cells as replication stress, activating damage-response pathways to bring about senescence.