Skorski, Tomasz2025-09-302025-09-302025-08https://scholarshare.temple.edu/handle/20.500.12613/11243Hematopoietic 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.133 pagesengIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.http://rightsstatements.org/vocab/InC/1.0/GeneticsCellular biologyCancer biologyGeneticsHematologyLeukemiaBiomedical sciencesText2025-09-02Atkins_temple_0225E_16268.pdf