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DNA POLYMERASE THETA COOPERATES WITH ADH5 AND ALDH2 DEHYDROGENASES TO PROTECT HEMATOPOIETIC CELLS FROM FORMALDEHYDE-MEDIATED DNA DAMAGE
Atkins, Jessica, Lynn
Atkins, Jessica, Lynn
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2025-08
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Biomedical Sciences
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Hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but can occasionally be challenged by high levels of formaldehyde generated by various endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks (DSBs) resulting from formaldehyde-mediated DNA-protein crosslinks (DPCs). Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemia cells. Thus, ADH5 and ALDH2 cooperate with Polθ to protect normal and malignant HSPCs challenged by high levels of formaldehyde and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.
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