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bioRxiv · 10.1101/591768

Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage

Gao, J.·Zou, J.·Li, J.·Zhang, Y.·Qiao, L.·Wang, F.·Bao, Y.·Hu, J.·Zhang, T.·Xie, Q.·Liu, C.
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Abstract

Folate contributes to the accumulation of DNA strand breaks (DSBs) in the genome. Kdm6a plays a critical role in early embryogenesis but it is unknown whether Kdm6a is involved in the DNA damage response under folate deficiency. Here, we established a low folate environment for mouse embryonic cells using a folate antagonist (methotrexate, MTX). We found increased enrichment of DSBs in Kdm6a in MTX-treated cells, resulting in reduced Kdm6a expression. MTX treatment enriched KDM6A in the nonhomologous end-joining (NHEJ) repair pathway and controlled the expression of the Ku heterodimer (Ku70/80) and XRCC4. The activation of NHEJ repair pathway-associated genes under folate deficiency relied on the specific interaction between KDM6A and p53. p53 silencing increased Ku heterodimer expression. In addition, in a neural tube defect (NTD) mouse model and low folate neural tube defect human brain samples, KDM6A levels were also decreased and accompanied by over-expression of Ku80. Our findings highlight how alterations in folate levels affect KDM6A with respect to DNA breakage and DNA repair, offering a new insight into the molecular function of KDM6A.\n\nSummary statementOur study demonstrates for the first time that in mammals, Kdm6a and p53 have synergistic effects during DNA fragmentation repair.

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Gao, J., Zou, J., Li, J., Zhang, Y., Qiao, L., Wang, F., Bao, Y., Hu, J., Zhang, T., Xie, Q., Liu, C.. 2019-03-28. Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage. https://doi.org/10.1101/591768

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