Folate deficiency induces dysfunctional long and short telomeres
The essential role of dietary micronutrients for genome stability is well documented, yet the effect of folate deficiency or excess on telomeres is not known. Accordingly, human WIL2-NS cells were maintained in medium containing 30nM, 300nM or 3000nM folic acid (FA) for 42 days to test the hypothesis that chronic folate deficiency would cause telomere shortening and dysfunction. After 14 days, telomere length (TL) in FA-deficient (30nM) cultures was 26% longer than that of 3000nM-FA cultures, however, this was followed by rapid telomere attrition over the subsequent 28 days (p-trend p<0.0001), both long and short telomere status was positively correlated with biomarkers of chromosome instability (p≤0.003) and mitotic dysfunction (p=0.01), measured by the cytokinesis-block micronucleus cytome assay. The early increase in TL was associated with FA-deficiency-induced global DNA hypomethylation (p=0.05), with an effect size similar to that induced by the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. qPCR analysis indicated a negative association between FA concentration and uracil incorporation into telomeric DNA (r = -0.47, p = 0.1), suggesting a possible plausible mechanism for uracil as a cause of folate deficiency-induced telomere dysfunction or deletion. PNA-FISH analysis showed FA-deficiency resulted in 60% of micronuclei containing acentric terminal fragments, an observation consistent with the 3-fold increase in terminal deletions (p=0.0001). Together these results demonstrate the impact of folate deficiency on biomarkers of telomere maintenance and integrity, and provide evidence that dysfunctional long telomeres may be as important as critically short telomeres as a cause of chromosomal instability
Bull CF, Mayrhofer G, O'Callaghan NJ, Au AY, Pickett HA, Low GK, Zeegers D, Hande MP, Fenech M. Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells. Cancer Prev Res (Phila). 2013 November Animal, Food and Health Sciences, CSIRO.