A Screen for Suppressors of Gross Chromosomal Rearrangements Identifies a Conserved Role for PLP in Preventing DNA Lesions

The faithful replication of the genome is necessary for maintenance of genome integrity. One class of genome aberrations prevalent in tumor cells is termed gross chromosomal rearrangements (GCRs), such as translocations, amplifications, inversions and deletions. They report the results of a genome-wide screen in Saccharomyces cerevisiae aimed at identifying novel suppressors of GCR formation. Nine novel genes were identified that increase the rate of genome instability in yeast when deleted. BUD16, encodes yeast pyridoxal kinase (Pdxk), was picked up as a most potent suppressor of GCR. Pdxk is an enzyme that is crucial for the metabolism of vitamin B6 to produce pyridoxal-5-phosphate (PLP), the biologically active form. PLP is an essential cofactor in dTMP synthesis pathway. PLP levels correlate with maintenance of genome integrity. Pharmacological inhibition of Pdxk induces DNA lesions and activation of the DNA damage response. Because Pdxk-deficient cells accumulate uracil in their nuclear DNA and are sensitive to inhibition of ribonucleotide reductase, PLP deficiency threatens genome integrity. Their work indicates that vitamin B6 metabolites are critical to maintain genome stability and hypothesizes that vitamin B6 reduces cancer risk by curtailing genome rearrangements. (Summarized by Dr. Naoko Abe, M.D.)

A Screen for Suppressors of Gross Chromosomal Rearrangements Identifies a Conserved Role for PLP in Preventing DNA Lesions
Pamela Kanellis, et al.
PLoS Genet August 2007 Volume 3 Issue 8: 1438-1453

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